N-alkyl-hydroxamic acid-isoindolyl compounds and their pharmaceutical uses

ABSTRACT

The invention encompasses novel N-alkyl-hydroxamic acid-isoindolyl compounds, pharmaceutical compositions of these compounds, and methods of using these compounds and compositions for treatment or prevention of various diseases and disorders, for example, diseases associated with PDE4.

[0001] This invention claims the benefit of U.S. Provisional ApplicationNo. 60/454,149, filed Mar. 12, 2003, which is incorporated herein in itsentirety by reference.

1. FIELD OF THE INVENTION

[0002] The invention encompasses novel N-alkyl-hydroxamicacid-isoindolyl compounds, pharmaceutical compositions of thesecompounds, and methods of using these compounds and compositions inmammals for the treatment, prevention and management of various diseasesand disorders, such as diseases mediated by PDE4 inhibition, associatedwith abnormal TNF-α levels, and/or mediated by MMP inhibition.

2. BACKGROUND OF THE INVENTION 2.1. TNF-α

[0003] Tumor necrosis factor alpha (TNF-α) is a cytokine that isreleased primarily by inflammation and mononuclear phagocytes inresponse to immunostimulators. TNF-α is capable of enhancing mostcellular processes, such as differentiation, recruitment, proliferation,and proteolytic degradation. At low levels, TNF-α confers protectionagainst infective agents, tumors, and tissue damage. However, TNF-α alsohas role in many diseases. When administered to mammals such as humans,TNF-α causes or aggravates inflammation, fever, cardiovascular effects,hemorrhage, coagulation, and acute phase responses similar to those seenduring acute infections and shock states. Enhanced or unregulated TNF-αproduction has been implicated in a number of diseases and medicalconditions, for example, cancers, such as solid tumors and blood-borntumors; heart disease, such as congestive heart failure; and viral,genetic, inflammatory, allergic, and autoimmune diseases.

[0004] Cancer is a particularly devastating disease, and increases inblood TNF-α levels are implicated in the risk of and the spreading ofcancer. Normally, in healthy subjects, cancer cells fail to survive inthe circulatory system, one of the reasons being that the lining ofblood vessels acts as a barrier to tumor-cell extravasation. However,increased levels of cytokines have been shown to substantially increasethe adhesion of cancer cells to endothelium in vitro. One explanation isthat cytokines, such as TNF-α stimulate the biosynthesis and expressionof a cell surface receptors called ELAM-1 (endothelial leukocyteadhesion molecule). ELAM-1 is a member of a family of calcium-dependentcell adhesion receptors, known as LEC-CAMs, which includes LECAM-1 andGMP-140. During an inflammatory response, ELAM-1 on endothelial cellsfunctions as a “homing receptor” for leukocytes. ELAM-1 on endothelialcells was shown to mediate the increased adhesion of colon cancer cellsto endothelium treated with cytokines (Rice et al., 1989, Science246:1303-1306).

[0005] Inflammatory diseases such as arthritis, related arthriticconditions (e.g., osteoarthritis and rheumatoid arthritis), inflammatorybowel disease, sepsis, psoriasis, chronic obstructive pulmonary diseasesand chronic inflammatory pulmonary diseases are also prevalent andproblematic ailments. TNF-α plays a central role in the inflammatoryresponse and the administration of their antagonists block chronic andacute responses in animal models of inflammatory disease.

[0006] Enhanced or unregulated TNF-α production has been implicated inviral, genetic, inflammatory, allergic, and autoimmune diseases.Examples of such diseases include, but are not limited to: HIV;hepatitis; adult respiratory distress syndrome; bone-resorptiondiseases; chronic obstructive pulmonary diseases; chronic pulmonaryinflammatory diseases; dermatitis; cystic fibrosis; septic shock;sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; postischemic reperfusion injury; meningitis; psoriasis; fibrotic disease;cachexia; graft versus host disease (GVHD); graft rejection; auto-immunedisease; rheumatoid spondylitis; arthritic conditions, such asrheumatoid arthritis, rheumatoid spondylitis and osteoarthritis;osteoporosis; inflammatory-bowel disease; Crohn's disease; ulcerativecolitis; multiple sclerosis; systemic lupus erythrematosus; ENL inleprosy; radiation damage; asthma; and hyperoxic alveolar injury. Traceyet al., 1987, Nature 330:662-664 and Hinshaw et al., 1990, Circ. Shock30:279-292 (endotoxic shock); Dezube et al., 1990, Lancet, 335:662(cachexia ); Millar et al., 1989, Lancet 2:712-714 and Ferrai-Balivieraet al., 1989, Arch. Surg. 124:1400-1405 (adult respiratory distresssyndrome); Bertolini et al., 1986, Nature 319:516-518, Johnson et al.,1989, Endocrinology 124:1424-1427, Holler et al., 1990, Blood75:1011-1016, and Grau et al., 1989, N. Engl. J. Med. 320:1586-1591(bone resorption diseases); Pignet et al., 1990, Nature, 344:245-247,Bissonnette et al., 1989, Inflammation 13:329-339 and Baughman et al.,1990, J. Lab. Clin. Med. 115:36-42 (chronic pulmonary inflammatorydiseases); Elliot et al., 1995, Int. J. Pharmac. 17:141-145 (rheumatoidarthritis); von Dullemen et al., 1995, Gastroenterology 109:129-135(Crohn's disease); Duh et al., 1989, Proc. Nat. Acad. Sci. 86:5974-5978,Poll et al., 1990, Proc. Nat. Acad. Sci. 87:782-785, Monto et al., 1990,Blood 79:2670, Clouse et al., 1989, J. Immunol. 142, 431-438, Poll etal., 1992, AIDS Res. Hum. Retrovirus, 191-197, Poli et al. 1990, Proc.Natl. Acad. Sci. 87:782-784, Folks et al., 1989, Proc. Nat. Acad. Sci.86:2365-2368 (HIV and opportunistic infections resulting from HIV).

2.2. PDE4

[0007] Adenosine 3′,5′-cyclic monophosphate (cAMP) also plays a role inmany diseases and conditions, such as, but not limited to asthma andinflammation (Lowe and Cheng, Drugs of the Future, 17(9), 799-807,1992). It has been shown that the elevation of cAMP in inflammatoryleukocytes inhibits their activation and the subsequent release ofinflammatory mediators, including TNF-α and nuclear factor κB (NF-κB).Increased levels of cAMP also lead to the relaxation of airway smoothmuscle.

[0008] It is believed that primary cellular mechanism for theinactivation of cAMP is the breakdown of cAMP by a family of isoenzymesreferred to as cyclic nucleotide phosphodiesterases (PDE) (Beavo andReitsnyder, Trends in Pharm., 11, 150-155, 1990). There are twelve knownmembers of the family of PDEs. It is recognized that the inhibition ofPDE type IV (PDE4) is particularly effective in both the inhibition ofinflammatory mediated release and the relaxation of airway smooth muscle(Verghese, et al., Journal of Pharmacology and ExperimentalTherapeutics, 272(3), 1313-1320, 1995). Thus, compounds thatspecifically inhibit PDE4 may inhibit inflammation and aid therelaxation of airway smooth muscle with a minimum of unwanted sideeffects, such as cardiovascular or anti-platelet effects.

[0009] The PDE4 family that is specific for cAMP is currently thelargest and is composed of at least 4 isozymes (a-d), and multiplesplice variants (Houslay, M. D. et al. in Advances in Pharmacology 44,eds. J. August et al., p.225, 1998). There may be over 20 PDE4 isoformsexpressed in a cell specific pattern regulated by a number of differentpromoters. Disease states for which selective PDE4 inhibitors have beensought include: asthma, atopic dermatitis, depression, reperfusioninjury, septic shock, toxic shock, endotoxic shock, adult respiratorydistress syndrome, autoimmune diabetes, diabetes insipidus,multi-infarct dementia, AIDS, cancer, Crohn's disease, multiplesclerosis, cerebral ischemia, psoriasis, allograft rejection,restenosis, ulceratiave colitis, cachexia, cerebral malaria, allergicrhino-conjunctivitis, osteoarthritis, rheumatoid arthrirtis, chronicobstructive pulmonary disease (COPD), chronic bronchitis, cosinophilicgranuloma, and autoimmune encephalomyelitis (Houslay et al., 1998). PDE4is present in the brain and major inflammatory cells and has been foundin abnormally elevated levels in a number of diseases including atopicdermatitis or eczema, asthma, and hay fever among others (reference OHSUflyer and J. of Allergy and Clinical Immunology, 70: 452-457, 1982 byGrewe et al.). In individuals suffering from atopic diseases elevatedPDE-4 activity is found in their peripheral blood mononuclearleukocytes, T cells, mast cells, neutrophils and basophils. Thisincreased PDE activity decreases cAMP levels and results in a breakdownof cAMP control in these cells. This results in increased immuneresponses in the blood and tissues of those that are affected.

[0010] Some PDE 4 inhibitors reportedly have a broad spectrumanti-inflammatory activity, with impressive activity in models ofasthma, chronic obstructive pulmonary disorder (COPD) and other allergicdisorders such as atopic dermatitis and hay fever. PDE 4 inhibitors thathave been used include theophylline, rolipram, denbufylline, ARIFLO,ROFLUMILAST, CDP 840 (a tri-aryl ethane) and CP80633 (a pyrimidone).PDE4 inhibitors have been shown to influence eosinophil responses,decrease basophil histamine release, decrease IgE, PGE2, IL10 synthesis,and decrease anti-CD3 stimulated I1-4 production. Similarly, PDE4inhibitors have been shown to block neutrophil functions. Neutrophilsplay a major role in asthma, chronic obstructive pulmonary disorder(COPD) and other allergic disorders. PDE4 inhibitors have been shown toinhibit the release of adhesion molecules, reactive oxygen species,interleukin (IL)-8 and neutrophil elastase, associated with neutrophilswhich disrupt the architecture of the lung and therefore airwayfunction. PDE4 inhibitors influence multiple functional pathways, act onmultiple immune and inflammatory pathways, and influence synthesis orrelease of numerous immune mediators. (J. M. Hanifin and S. C. Chan,“Atopic Dermatitis-Therapeutic Implication for New PhosphodiesteraseInhibitors,” Monocyte Dysregulation of T Cells in AACI News, 7/2, 1995;J. M. Hanifin et al., “Type 4 Phosphodiesterase Inhibitors Have clinicaland In vitro Anti-inflammatory Effects in Atopic Dermatitis,” Journal ofInvestigative Dermatology, 1996, 107, pp51-56).

[0011] Some of the first generation of PDE-4 inhibitors are effective ininhibiting PDE4 activity and alleviating a number of the inflammatoryproblems caused by over expression of this enzyme. However, theireffectiveness is limited by side effects, particularly when usedsystemically, such as nausea and vomiting. Huang et al., Curr. Opin. InChem. Biol., 2001, 5:432-438. Indeed, all of the PDE4 inhibitorsdeveloped to date have been small molecule compounds with centralnervous system and gastrointestinal side effects, e.g., headache,nausea/emesis, and gastric secretion.

2.3. MMP

[0012] Matrix metalloproteinases (MMPs) are a family of proteases(enzymes) involved in the degradation and remodeling of connectivetissues. Excessive degradation of extracellular matrix by MMPs isimplicated in the pathogenesis of many diseases, including rheumatoidarthritis, osteoarthritis, cancer, multiple sclerosis, bone resorptivediseases (such as osteoporosis), chronic obstructive pulmonary disease,restenosis, cerebral hemorrhaging associated with stroke, periodontaldisease, aberrant angiogenesis, tumor invasion and metastasis, cornealand gastric ulceration, ulceration of skin, aneurysmal disease, and incomplications of diabetes. MMP inhibition is, therefore, recognized as agood target for therapeutic intervention of this type of diseases. Manycompounds having MMP inhibition activities have been reported (R. A.Nigel et al., Current Opinion on Therapeutic Patents, Vol. 4, 7-16,(1994), R. P. Beckett et al., Drug Discovery Today, Vol. 1, 16-26,(1996)). However, most are peptide derivatives based on the amino acidsequence of the enzymatic cleavage site in the collagen moleculeconstituting the substrate of MMP. A need exists for small moleculeinhibitors of MMP.

3. SUMMARY OF THE INVENTION

[0013] The present invention provides compounds which are useful in thetreatment of diseases mediated by the inhibition of PDE4, as well asdiseases mediated by TNF-α and MMP. The invention also providespharmaceutical compositions comprising these compounds and methods ofusing them for the treatment of a variety of diseases.

[0014] One embodiment of this invention encompasses compounds of formula(I):

[0015] wherein:

[0016] Y is —C(O)—, —CH₂—, —CH₂C(O)— or —SO₂—;

[0017] R₁ and R₂ are each independently C₁₋₈-alkyl, CF₂H, CF₃, CH₂CHF₂,cycloalkyl, or (C₁₋₈-alkyl)cycloalkyl;

[0018] Z₁ is H, C₁₋₆-alkyl, NH₂, NR₃R₄ or OR₅;

[0019] Z₂ is H or C(O)R₅;

[0020] X₁, X₂, X₃ and X₄ are each independently H, halogen, NO₂, OR₃,CF₃, C₁₋₆-alkyl, (C₀₋₄-alkyl)-(C₃₋₆-cycloalkyl), (C₀₋₄-alkyl)-N—(R₈R₉),(C₀₋₄-alkyl)-NHC(O)—(R₈), (C₀₋₄-alkyl)-NHC(O)CH(R₈)(R₉),(C₀₋₄-alkyl)-NHC(O)N(R₈R₉), (C₀₋₄-alkyl)-NHC(O)O(R₈), (C₀₋₄-alkyl)-O—R₈,(C₀₋₄-alkyl)-imidazolyl, (C₀₋₄-alkyl)-pyrrolyl,(C₀₋₄-alkyl)-oxadiazolyl, (C₀₋₄-alkyl)-triazolyl or(C₀₋₄-alkyl)-heterocycle;

[0021] R₃, R₄, and R₅ are each independently H, C₁₋₆-alkyl,O—C₁₋₆-alkyl, phenyl, benzyl, or aryl;

[0022] R₆ and R₇ are each independently H or C₁₋₆-alkyl;

[0023] R₈ and R₉ are each independently H, C₁₋₉-alkyl, C₃₋₆-cycloalkyl,(C₁₋₆-alkyl)-(C₃₋₆-cycloalkyl), (C₀₋₆-alkyl)-N(R₄R₅), (C₁₋₆-alkyl)-OR₅,phenyl, benzyl, aryl, piperidinyl, piperizinyl, pyrolidinyl, morpholino,or C₃₋₇-heterocycloalkyl; and

[0024] and pharmaceutically acceptable salts, solvates, hydrates,stereoisomers, clathrates, or prodrugs thereof.

[0025] Another embodiment of the invention encompasses a method ofmodulating (e.g., inhibiting the production of or lowering the levelsof) PDE4 in a mammal or a mammalian cell comprising administering tosaid mammal or mammalian cell an effective amount of a compound of theinvention (e.g., a compound of formula I).

[0026] In another embodiment, the invention encompasses a method ofmodulating the production of, or lowering the levels of, TNF-α in amammal or a mammalian cell comprising administering to said mammal ormammalian cell an effective amount of a compound of the invention.

[0027] In yet another embodiment, the invention encompasses a method ofmodulating the production, in particular, inhibiting or lowering thelevels of MMP in a mammal or a mammalian cell comprising administeringto said mammal or mammalian cell an effective amount of a compound ofthe invention.

[0028] Other embodiments of the invention encompass methods of treating,preventing and managing various disease or disorders, such as, but notlimited to: central nervous system (CNS) disorders; myelodysplasticsyndrome (MDS) and related syndromes; complex regional pain syndrome(CRPS) and related syndromes; cancer and related diseases; maculardegeneration (MD) and related syndromes; myeloproliferative diseases(MPD) and related syndromes; and asbestos-related diseases anddisorders.

[0029] Pharmaceutical compositions, modes of administration,formulations, and methods of using the above compounds alone or incombination are described in more detail below.

3.1. Abbreviations and Definitions

[0030] The abbreviations used herein are conventional, unless otherwisedefined.

[0031] The terms “treat,” “treating” and “treatment,” as used herein,contemplate an action that occurs while a patient is suffering from thespecified disease or disorder, which reduces the severity of the diseaseor disorder.

[0032] As used herein, unless otherwise indicated, the terms “prevent,”“preventing” and “prevention” contemplate an action that occurs before apatient begins to suffer from the specified disease or disorder, whichinhibits or reduces the severity of the disease or disorder.

[0033] As used herein, and unless otherwise indicated, the terms“manage,” “managing” and “management” encompass preventing therecurrence of the specified disease or disorder in a patient who hasalready suffered from the disease or disorder, and/or lengthening thetime that a patient who has suffered from the disease or disorderremains in remission. The terms encompass modulating the threshold,development and/or duration of the disease or disorder, or changing theway that a patient responds to the disease or disorder.

[0034] The term “therapeutically effective amount” refers to that amountof the compound being administered sufficient to prevent development ofor alleviate to some extent one or more of the symptoms of the conditionor disorder being treated as well as to alleviate or eradicate the causeof the disease itself.

[0035] As used herein, the term “PDE4-responsive condition or disorder”or “mediated by PDE4 inhibition” or “mediated by inhibition of PDE4”refers to a condition or disorder that responds favorably to modulationof PDE4 activity. Favorable responses to PDE4 modulation includealleviation or abrogation of the disease and/or its attendant symptoms,inhibition of the disease, i.e., arrest or reduction of the developmentof the disease, or its clinical symptoms, and regression of the diseaseor its clinical symptoms. A PDE4-responsive condition or disease may becompletely or partially responsive to PDE4 modulation. A PDE4-responsivecondition or disorder may be associated with inappropriate, e.g., lessthan or greater than normal, PDE4-activity. Inappropriate PDE4functional activity might arise as the result of PDE4 expression incells which normally do not express PDE4, decreased PDE4 expression(leading to, e.g., lipid and metabolic disorders and diseases) orincreased PDE4 expression. A PDE4-responsive condition or diseaseincludes a PDE4-mediated condition or disease.

[0036] The term “alkyl,” by itself or as part of another substituent,means, unless otherwise stated, a straight or branched chain, acyclic orcyclic hydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multi-valentradicals, having the number of carbon atoms designated (e.g., C₀₋₁₀means one to ten carbons, or not present, i.e., C₀ means the moeity doesnot exist). Examples of saturated hydrocarbon radicals include groupssuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologsand isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, andthe like. An unsaturated alkyl group is one having one or more doublebonds or triple bonds. Examples of unsaturated alkyl groups includevinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. The term “alkyl,” unlessotherwise noted, is also meant to include those derivatives of alkyldefined in more detail below as “heteroalkyl,” “cycloalkyl” and“alkylene.” The term “alkylene” by itself or as part of anothersubstituent means a divalent radical derived from an alkane, asexemplified by —CH₂CH₂CH₂CH₂—. Typically, an alkyl group will have from1 to 24 carbon atoms, with those groups having 10 or fewer carbon atomsbeing preferred in the present invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingeight or fewer carbon atoms.

[0037] The term “heteroalkyl,” by itself or in combination with anotherterm, means, unless otherwise stated, a stable straight or branchedchain, acyclic or cyclic hydrocarbon radical, or combinations thereof,consisting of the stated number of carbon atoms and from one to threeheteroatoms selected from the group consisting of O, N, Si and S, andwherein the nitrogen and sulfur atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quaternized. The heteroatom(s) O,N and S may be placed at any interior position of the heteroalkyl group.The heteroatom Si may be placed at any position of the heteroalkylgroup, including the position at which the alkyl group is attached tothe remainder of the molecule. Examples include —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Also included in the term“heteroalkyl” are those radicals described in more detail below as“heteroalkylene” and “heterocycloalkyl.” The term “heteroalkylene” byitself or as part of another substituent means a divalent radicalderived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can alsooccupy either or both of the chain termini. For alkylene andheteroalkylene linking groups, no orientation of the linking group isimplied.

[0038] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves orin combination with other terms, represent, unless otherwise stated,cyclic versions of “alkyl” and “heteroalkyl,” respectively. Thus, theterms “cycloalkyl” and “heterocycloalkyl” are meant to be included inthe terms “alkyl” and “heteroalkyl,” respectively. Furthermore, the term“C₃₋₁₈ cycloalkyl” means a cycloalkyl with 3 to 18 carbon atoms.Additionally, for heterocycloalkyl, a heteroatom can occupy the positionat which the heterocycle is attached to the remainder of the molecule.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.Examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl),1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl,3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl,2-piperazinyl, and the like.

[0039] The terms “halo” or “halogen,” by themselves or as part ofanother substituent, mean, unless otherwise stated, a fluorine,chlorine, bromine, or iodine atom. Additionally, terms such as“haloalkyl,” are meant to include alkyl substituted with halogen atomswhich can be the same or different, in a number ranging from one to(2m′+1), where m′ is the total number of carbon atoms in the alkylgroup. For example, the term “halo(C₁-₄)alkyl” includes trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Thus,the term “haloalkyl” includes monohaloalkyl (alkyl substituted with onehalogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms ina number ranging from two to (2m′+1) halogen atoms, where m′ is thetotal number of carbon atoms in the alkyl group). The term“perhaloalkyl” means, unless otherwise stated, alkyl substituted with(2m′+1) halogen atoms, where m′ is the total number of carbon atoms inthe alkyl group. For example, the term “perhalo(C₁-₄)alkyl” includestrifluoromethyl, pentachloroethyl,1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

[0040] The term “aryl,” employed alone or in combination with otherterms (e.g., aryloxy, arylthioxy, arylalkyl) means, unless otherwisestated, an aromatic substituent which can be a single ring or multiplerings (up to three rings) which are fused together or linked covalently.The rings may each contain from zero to four heteroatoms selected fromN, O, and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. The arylgroups that contain heteroatoms may be referred to as “heteroaryl” andcan be attached to the remainder of the molecule through a heteroatom.Non-limiting examples of aryl groups include phenyl, 1-naphthyl,2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, oxadiazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl,5-indolyl, triazolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl,5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of theabove noted aryl ring systems are selected from the group of acceptablesubstituents described below.

[0041] The term “arylalkyl” includes those radicals in which an arylgroup is attached to an alkyl group (e.g., benzyl, phenethyl,pyridylnethyl and the like) or a heteroalkyl group (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

[0042] Each of the above terms (e.g., “alkyl,” “heteroalkyl” and “aryl”)includes both substituted and unsubstituted forms of the indicatedradical. Preferred substituents for each type of radical are providedbelow.

[0043] Substituents for the alkyl and heteroalkyl radicals (includingthose groups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be a variety of groups selected from: —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —CN and —NO₂ in a number ranging from zero to (2N+1), whereN is the total number of carbon atoms in such radical, and where R′, R″and R′″ each independently refer to hydrogen, unsubstituted(C₁-₈)alkyland heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens,unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C₁-₄)alkylgroups. When R′ and R″ are attached to the same nitrogen atom, they canbe combined with the carbon atoms to which they are attached with thenitrogen atom to form a 5-, 6- or 7-membered ring containing from 1 to 3heteroatoms selected from the group consisting of N, O and S. Forexample, —NR′R″ includes 1-pyrrolidinyl and 4-morpholinyl. From theabove discussion of substituents, one of skill in the art willunderstand that the term “alkyl” includes substituted alkyl groupsincluding haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g., —C(O)CH₃,—C(O)CF₃, and —C(O)CH₂OCH₃).

[0044] Similarly, substituents for the aryl groups are varied and can beselected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂,—CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —N₃, —CH(Ph)₂, fluoro(C₁-₄)alkoxy, andfluoro(C₁-₄)alkyl, in a number ranging from zero to the total number ofopen valences on the aromatic ring system; and where each R′, R″ and R′″is hydrogen, (C₁-₈)alkyl and heteroalkyl, unsubstituted aryl,(unsubstituted aryl)-(C₁-₄)alkyl or (unsubstituted aryl)oxy-(C₁-₄)alkyl.

[0045] As used herein, the term “heteroatom” includes oxygen (O),nitrogen (N) and sulfur (S). In certain embodiments, the term furtherencompasses silicon (Si).

[0046] The term “pharmaceutically acceptable salt” includes salts whichare prepared with relatively nontoxic acids or bases, depending on theparticular substituents found on the compounds described herein. Whencompounds of the present invention contain relatively acidicfunctionalities, base addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredbase, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable base addition salts include sodium,potassium, calcium, ammonium, organic amino and magnesium salts. Whencompounds of the present invention contain relatively basicfunctionalities, acid addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredacid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, nitric,carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic andphosphorous acids, as well as the salts derived from relatively nontoxicorganic acids such as acetic, propionic, isobutyric, oxalic, maleic,malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic,benzenesulfonic, p-tolylsulfonic, citric, tartaric and methanesulfonicacids. Also included are salts of amino acids, such as arginate, andsalts of organic acids such as glucuronic and galactunoric acids. See,e.g., Berge et al. (1977) J. Pharm. Sci. 66:1-19. Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

[0047] Neutral forms of some compounds may be regenerated by contactingthe salt with a base or acid and isolating the parent compound in theconventional manner. The parent form of a compound can differ from itsvarious salt forms in certain physical properties, such as solubility inpolar solvents, but the salts are typically equivalent to the parentform of the compound for the purposes of the present invention.

[0048] Certain compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, solvated forms are pharmacologically equivalent to unsolvatedforms. Certain compounds of the invention may exist in multiplecrystalline or amorphous forms. In general, all physical forms areequivalent for the uses contemplated by this invention, and areencompassed by this invention.

[0049] Certain compounds of the present invention possess asymmetriccarbon atoms (optical or stereo-centers) or double bonds. The racemates,enantiomers, diastereomers, geometric isomers and mixtures thereof areall intended to be encompassed by the present invention.

[0050] Compounds of the invention may also contain unnatural proportionsof atomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as tritium (³H), iodine-125 (¹²⁵I) andcarbon-14 (¹⁴C). Radiolabeled compounds are useful as therapeuticagents, e.g., cancer therapeutic agents, research reagents, e.g., assayreagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of the compounds of the present invention, whetherradioactive or not, are intended to be encompassed within the scope ofthe present invention.

4. DETAILED DESCRIPTION OF THE INVENTION

[0051] The invention encompasses novel compounds and compositionsthereof that can be used to treat, prevent or manage diseases in mammals(e.g., humans). Examples of such diseases or disorders include, but arenot limited to, cancer; viral, genetic, inflammatory, allergic, andautoimmune diseases; and bacterial infections. Compounds of theinvention can be used to treat, prevent or manage diseases caused oraggravated by excessive, insufficient or unregulated levels of PDE4,TNF-α or MMP. More specific examples include, but are not limited to:central nervous system (CNS) disorders; myelodysplastic syndrome (MDS)and related syndromes; complex regional pain syndrome (CRPS) and relatedsyndromes; cancer and related diseases; macular degeneration (MD) andrelated syndromes; myeloproliferative diseases (MPD) and relatedsyndromes; and asbestos-related diseases or disorders.

[0052] The invention encompasses compounds of formula (I):

[0053] wherein:

[0054] Y is —C(O)—, —CH₂—, —CH₂C(O)— or —SO₂—;

[0055] R₁ and R₂ are each independently C₁₋₈-alkyl, CF₂H, CF₃, CH₂CHF₂,cycloalkyl, or (C₁₋₈-alkyl)cycloalkyl;

[0056] Z₁ is H, C₁₋₆-alkyl, NH₂, NR₃R₄ or OR₅;

[0057] Z₂ is H or C(O)R₅;

[0058] X₁, X₂, X₃ and X₄ are each independently H, halogen, NO₂, OR₃,CF₃, C₁₋₆-alkyl, (C₀₋₄-alkyl)-(C₃₋₆-cycloalkyl), (C₀₋₄-alkyl)-N—(R₈R₉),(C₀₋₄-alkyl)-NHC(O)—(R₈), (C₀₋₄-alkyl)-NHC(O)CH(R₈)(R₉),(C₀₋₄-alkyl)-NHC(O)N(R₈R₉), (C₀₋₄-alkyl)-NHC(O)O(R₈), (C₀₋₄-alkyl)-O—R₈,(C₀₋₄-alkyl)-imidazolyl, (C₀₋₄-alkyl)-pyrrolyl,(C₀₋₄-alkyl)-oxadiazolyl, (C₀₋₄-alkyl)-triazolyl or(C₀₋₄-alkyl)-heterocycle;

[0059] R₃, R₄, and R₅ are each independently H, C₁₋₆-alkyl,O—C₁₋₆-alkyl, phenyl, benzyl, or aryl;

[0060] R₆ and R₇ are each independently H or C₁₋₆-alkyl;

[0061] R₈ and R₉ are each independently H, C₁₋₉-alkyl, C₃₋₆-cycloalkyl,(C₁₋₆-alkyl)-(C₃₋₆-cycloalkyl), (C₀₋₆-alkyl)-N(R₄R₅), (C₁₋₆-alkyl)-OR₅,phenyl, benzyl, aryl, piperidinyl, piperizinyl, pyrolidinyl, morpholino,or C₃₋₇-heterocycloalkyl;

[0062] and pharmaceutically acceptable salts, solvates, hydrates,stereoisomers, clathrates, or prodrugs thereof.

[0063] In a preferred embodiment, Y is —CH₂— or —C(O)—.

[0064] In another preferred embodiment, Z₁ is H.

[0065] In another preferred embodiment, Z₁ is H and R₆ is C₁₋₆-alkyl andR₇ is H.

[0066] In another preferred embodiment, Z₂ is H, —C(O)CH₃ or—C(O)CH₂CH₃.

[0067] In another preferred embodiment, Z₂ is H, —C(O)CH₃ or —C(O)CH₂CH₃and X₄ is NHC(O)R₅.

[0068] In another preferred embodiment, Z₂ is H, —C(O)CH₃ or —C(O)CH₂CH₃and R₁ CH₃ or CHF₂ and R₂ is C₁₋₈-alkyl.

[0069] In another preferred embodiment, Z₂ is H.

[0070] In still another preferred embodiment, R₁ is CH₃ or CF₂H.

[0071] In yet another preferred embodiment, R₂ is CH₂CH₃, CH₃, CF₂H,CH₂— cyclopropyl, or cyclopentyl.

[0072] In another preferred embodiment, R₆ and R₇ are both H or one ofR₆ and R₇ is H and the other is CH₃.

[0073] In a further preferred embodiment, X₄ is —NHC(O)R₄ and X₁ is H orhalogen.

[0074] In still another preferred embodiment of X₁, X₂, X₃, and X₄ isNHCOCH₂N(CH₃)₂, NHCON(CH₃)₂, NHCONH₂, NHCOCH₃, NHCOCH(R₈)N(R₈R₉) or OCH₃and, the rest are H.

[0075] Exemplary compounds of the invention include, but are not limitedto, those listed in Table I below: TABLE I Example No. Compound Name 4

(3R)-(tert-Butoxy)-N-{3-[7-(cyclo- propylcarbonylamino)-1-oxo-isoindolin-2-yl]-3-(3-eth- oxy-4-meth- oxyphenyl)propyl}carbon-ylamino(tert-butoxy)formate 5

N-[3-(7-AmIno-1-oxo- isoindolin-2-yl)-3-(3-eth- oxy-4-meth-oxyphenyl)propyl](tert- butoxy)carbonylamino(tert- butoxy)formate 7

(1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-meth-oxy-phenyl)-3-(N-for- myl-N-hydroxy-amino)-pro-pyl]-3-oxo-2,3-dihydro-1H-Iso- indol-4-yl}-amide 8

(1R)-N-{2-[1-(3-Ethoxy-4-meth- oxy-phenyl)-3-(N-for-myl-N-hydroxy-amino)-pro- pyl]-3-oxo-2,3-dihydro-1H-Iso-indol-4-yl}-acetamide 9

(1R)-N-{2-[1-(3-Ethoxy-4-meth- oxy-phenyl)-3-(N-for-myl-N-hydroxy-amino)-pro- pyl]-3-oxo-2,3-dihydro-1H-Iso-indol-4-yl}-Iso- butyramide 10

(1R)-N-{2-[1-(3-Ethoxy-4-meth- oxy-phenyl)-3-(N-for-myl-N-hydroxy-amino)-pro- pyl]-1,3-dioxo-2,3-di-hydro-1H-Isoindol-4-yl}-aceta- mide 11

(1R)-N-{2-[3-(N-Acetoxy-N-for- myl-amino)-1-(3-ethoxy-4-meth-oxy-phenyl)-propyl]-3-oxo-2,3-di- hydro-1H-Isoindol-4-yl}-Iso-butyramide 12

(1R)-N-{2-[3-(N-Amino- carbonyl-N-hydroxy-ami- no)-1-(3-ethoxy-4-meth-oxy-phenyl)-propyl]-3-oxo-2,3-dI- hydro-1H-Isoindol-4-yl}-Iso-butyramide 13

(1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-meth-oxy-phenyl)-3-(N-for- myl-N-hydroxy-amino)-pro-pyl]-3-oxo-2,3-dihydro-1H-Iso- indol-4-yl}-amide 14

(N-{3-[7-(Cyclo- propylcarbonylamino)-1-oxo- isoindolin-2-yl]-3-(3-eth-oxy-4-meth- oxyphenyl)propyl}acetyl amino)acetate 15

(1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-meth-oxy-phenyl)-3-(formyl-hy- droxy-amino)-butyl]-3-oxo-2,3-di-hydro-1H-Isoindol-4-yl}-amide

[0076] Compounds of the invention generally exist in solid form and canbe recrystallized according to well-known methods affording high-puritycrystals, preferably, in greater than 95% purity, more preferably, ingreater than 98% purity. A narrow melting-point range is often anindication of purity. Thus, preferred compounds of the invention have amelting point within a range of 3° C. to 4° C., more preferably, withina range of 2° C.

[0077] Various compounds of the invention contain one or more chiralcenters, and can exist as racemic mixtures of enantiomers or mixtures ofdiastereomers. This invention encompasses the use of stereomericallypure forms of such compounds, as well as the use of mixtures of thoseforms. For example, mixtures comprising equal or unequal amounts of theenantiomers of a particular compounds of the invention may be used inmethods and compositions of the invention. These isomers may beasymmetrically synthesized or resolved using standard techniques such aschiral columns or chiral resolving agents. See, e.g., Jacques, J., etal., Enantiomers, Racemates and Resolutions (Wiley-Interscience, NewYork, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); andWilen, S. H., Tables of Resolving Agents and Optical Resolutions, p. 268(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

[0078] Compounds of the invention can contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers and geometircisomers. Chemical structures and portions of chemical structuresdepicted herein encompass all of their enantiomers and stereoisomers,e.g., both the stereomerically pure forms stereoisomeric mixtures.

[0079] As used herein, and unless otherwise indicated, the term“stereomerically pure” or “enantiomerically pure” means that a compoundcontains one stereoisomers and is substantially free of its counterstereoisomer or enantiomer. For example, a compound is stereomericallyor eneantiomerically pure when the compound contains 80%, 90%, or 95% ormore of one stereoisomer and 20%, 10%, or 5% or less of the counterstereoisomer. In certain cases, a compound of the invention isconsidered optically active or enantiomerically pure (i.e.,substantially the R-form or substantially the S-form) with respect to achiral center when the compound is about 80% ee (enantiomeric excess) orgreater, preferably, equal to or greater than 90% ee with respect to aparticular chiral center, and more preferably 95% ee with respect to aparticular chiral center.

[0080] As used herein, and unless otherwise indicated, the term“stereoisomeric mixture” encompasses racemic mixtures as well asstereomerically enriched mixtures (e.g., R/S=30/70, 35/65, 40/60, 45/55,55/45, 60/40, 65/35 and 70/30).

[0081] Compound of formula I have at least one stereocenter, identifiedbelow as a:

[0082] In addition, when R₆ is not the same as R₇, compounds of formulaI have an additional stereocenter denoted as b. Further, compounds offormula I may have additional stereocenters depending on the particularsubstituents at various positions on the structure. This inventionencompasses stereomerically pure compounds of formula I, as well asmixtures of those compounds (e.g., racemic and stereomerically enrichedmixtures)

[0083] In one embodiment, the invention encompasses compounds of formulaI, wherein the configuration of stereocenter a is (S).

[0084] In another embodiment, the invention encompasses compounds offormula I, wherein the configuration of stereocenter a is (R).

[0085] In another embodiment, the invention encompasses compounds offormula I, wherein R₆ and R₇ are not same, and the configuration ofstereocenter b is (S).

[0086] In another embodiment, the invention encompasses compounds offormula I, wherein R₆ and R₇ are not same, and the configuration ofstereocenter b is (R).

[0087] Where R₆ and R₇ are not same, compounds of formula I have atleast two chiral centers, and thus may exist in diastereomerically pureforms. As used herein, in two letter symbols that denote diastereomericconfiguration, the first letter refers to the configuration of chiralcenter a, and the second letter refers to the configuration of chiralcenter b. For example, configuration RS, when used in connection withcompounds of formula I, refers to a configuration wherein chiral centera is in R and chiral center b is in S configurations.

[0088] In a related embodiment, the invention encompasses adiasteriomerically pure RR isomer of a compound of formula I,substantially free of other diasteromers.

[0089] In another embodiment, the invention encompasses adiasteriomerically pure RS isomer of a compound of formula I,substantially free of other diasteromers.

[0090] In another related embodiment, the invention encompasses adiasteriomerically pure SR isomer of a compound of formula I,substantially free of other diasteromers.

[0091] In still another embodiment, the invention encompasses adiasteriomerically pure SS isomer of a compound of formula I,substantially free of other diasteromers.

[0092] Enantiomeric and stereoisomeric mixtures of compounds of theinvention can be resolved into their component enantiomers orstereoisomers by well-known methods, such as chiral-phase gaschromatography, chiral-phase high performance liquid chromatography,crystallizing the compound as a chiral salt complex, or crystallizingthe compound in a chiral solvent. Enantiomers and stereoisomers can alsobe obtained from stereomerically or enantiomerically pure intermediates,reagents, and catalysts by well-known asymmetric synthetic methods.

[0093] The invention further encompasses prodrugs of compoundsencompassed by formula I. As used herein, and unless otherwiseindicated, the term “prodrug” means a derivative of a compound that canhydrolyze, oxidize, or otherwise react under biological conditions (invitro or in vivo) to provide the compound. Examples of prodrugs include,but are not limited to, derivatives of compounds of the invention thatcomprise biohydrolyzable moieties such as biohydrolyzable amides,biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, and biohydrolyzable phosphateanalogues. Other examples of prodrugs include derivatives of compoundsof the invention that comprise —NO, —NO₂, —ONO, or —ONO₂ moieties.Prodrugs can typically be prepared using well-known methods, such asthose described in Burger's Medicinal Chemistry and Drug Discovery,172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design ofProdrugs (H. Bundgaard ed., Elselvier, N.Y. 1985).

[0094] As used herein and unless otherwise indicated, the terms“biohydrolyzable amide,” “biohydrolyzable ester,” “biohydrolyzablecarbamate,” “biohydrolyzable carbonate,” “biohydrolyzable ureide,”“biohydrolyzable phosphate” mean an amide, ester, carbamate, carbonate,ureide, or phosphate, respectively, of a compound that either: 1) doesnot interfere with the biological activity of the compound but canconfer upon that compound advantageous properties in vivo, such asuptake, duration of action, or onset of action; or 2) is biologicallyinactive but is converted in vivo to the biologically active compound.Examples of biohydrolyzable esters include, but are not limited to,lower alkyl esters, lower acyloxyalkyl esters (such as acetoxylmethyl,acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, andpivaloyloxyethyl esters), lactonyl esters (such as phthalidyl andthiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such asmethoxycarbonyloxymethyl, ethoxycarbonyloxyethyl andisopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters,and acylamino alkyl esters (such as acetamidomethyl esters). Examples ofbiohydrolyzable amides include, but are not limited to, lower alkylamides, -amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamatesinclude, but are not limited to, lower alkylamines, substitutedethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic andheteroaromatic amines, and polyether amines.

[0095] The compounds of the invention are defined herein by theirchemical structures and/or chemical names. Where a compound is referredto by both a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure is to beaccorded more weight.

[0096] This invention provides pharmaceutical compositions comprising atherapeutically effective or a prophylactically effective amount of oneor more compounds of the invention and a pharmaceutically acceptablevehicle or carrier. A pharmaceutically acceptable vehicle or carrier cancomprise an excipient, diluent, or a mixture thereof. The term“therapeutically effective amount” means the amount of a compound of theinvention that will elicit the biological or medical response in amammal that is being that is being treated by the veterinarian orclinician. The term “prophylactically effective” means the amount of acompound of the invention that will prevent or inhibit affliction ormitigate affliction of a mammal with a medical condition that aveterinarian or clinician is trying to prevent, inhibit, or mitigate.

[0097] In another embodiment, the invention encompasses a methodinhibiting PDE4 in a mammal comprising administering to said mammal aneffective amount of a compound of the invention.

[0098] In another embodiment, the invention encompasses a method ofmodulating the production or lowering the levels of TNF-α in a mammalcomprising administering to said mammal an effective amount of acompound of the invention.

[0099] In yet another embodiment, the invention encompasses a method ofinhibiting MMP in a mammal comprising administering to said mammal aneffective amount of a compound of the invention.

[0100] In yet another embodiment, the invention encompasses a method oftreating undesired angiogenesis in a mammal comprising administering tosaid mammal an effective amount of a compound of the invention. Diseasesassociated with angiogenesis are well known in the art.

[0101] A separate embodiment of the invention encompasses methods oftreating, preventing or managing Myelodysplastic Syndrome (MDS) whichcomprises administering to a patient in need of such treatment orprevention a therapeutically or prophylactically effective amount of acompound of the invention, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. MDSrefers to a diverse group of hematopoietic stem cell disorders. MDS ischaracterized by a cellular marrow with impaired morphology andmaturation (dysmyelopoiesis), peripheral blood cytopenias, and avariable risk of progression to acute leukemia, resulting fromineffective blood cell production. The Merck Manual 953 (17th ed. 1999)and List et al., 1990, J. Clin. Oncol. 8:1424.

[0102] Another separate embodiment of the invention encompasses methodsof treating, preventing or managing macular degeneration (MD), whichcomprises administering to a patient in need of such treatment,prevention or management a therapeutically or prophylactically effectiveamount of a compound of the invention, or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. MDrefers to an eye disease that destroys central vision by damaging themacula.

[0103] A separate embodiment of the invention encompasses methods oftreating, preventing or managing Myeloproliferative Disease (MPD) whichcomprises administering to a patient in need of such treatment orprevention a therapeutically or prophylactically effective amount of acompound of the invention, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.Myeloproliferative Disease (MPD) refers to a group of disorderscharacterized by clonal abnormalities of the hematopoietic stem cell.See e.g., Current Medical Diagnosis & Treatment, pp. 499 (37th ed.,Tierney et al. ed, Appleton & Lange, 1998).

[0104] The invention also encompasses a method of treating, preventingor managing Complex Regional Pain Syndrome (CRPS), which comprisesadministering to a patient in need of such treatment, prevention ormanagement a therapeutically or prophylactically effective amount of acompound of the invention, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, before,during or after surgery or physical therapy directed at reducing oravoiding a symptom of complex regional pain syndrome in the patient.

[0105] In another embodiment, this invention encompasses a method oftreating, preventing or managing a central nervous system (CNS)disorder, which comprises administering to a patient in need of suchtreatment, prevention or management a therapeutically orprophylactically effective amount of a compound of the invention, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof.

[0106] In another embodiment, this invention encompasses a method oftreating, preventing or managing an asbestos-related disease ordisorder, which comprises administering to a patient in need of suchtreatment, prevention or management a therapeutically orprophylactically effective amount of a compound of the invention, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof. Asbestos-related disease or disorderrefers to a disease or disorder caused by an exposure to asbestos.

[0107] The invention also encompasses a method of treating, preventingor managing Parkinson's disease or a related disorder, which comprisesadministering to a patient in need of such treatment, prevention ormanagement a therapeutically or prophylactically effective amount of acompound of the invention, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

[0108] In still another embodiment, the invention encompasses a methodof treating, preventing or managing cancer in a mammal, comprisingadministering to said mammal a therapeutically effective amount of acompound of the invention. The compounds of the invention can be used totreat, prevent or manage any cancer, for example, solid tumors andblood-born tumors. Specific examples of cancers treatable, preventableor manageable by compounds of the invention include, but are not limitedto, cancers of the skin, such as melanoma; lymph node; breast; cervix;uterus; gastrointestinal tract; lung; ovary; prostate; colon; rectum;mouth; brain; head and neck; throat; testes; kidney; pancreas; bone;spleen; liver; bladder; larynx; nasal passages; and AIDS-relatedcancers. The compounds are particularly useful for treating cancers ofthe blood and bone marrow, such as multiple myeloma and acute andchronic leukemias, for example, lymphoblastic, myelogenous, lymphocytic,and myelocytic leukemias. The compounds of the invention can be used fortreating, preventing or managing either primary or metastatic tumors.

[0109] In yet one more embodiment, the invention encompasses methods oftreating, preventing or managing cancer in a mammal, comprisingadministering to a mammal in need thereof, a therapeutically effectiveamount of a compound of the invention and another therapeutic agent.

[0110] In yet another embodiment, the invention encompasses a method oftreating, preventing or managing inflammatory disorders in a mammal,comprising administering to said mammal a therapeutically effectiveamount of a compound of the invention. The compounds of the inventionare especially effective to treat, prevent or manage inflammatorydiseases related to the up-regulation of TNF-α including, but notlimited to, arthritic conditions, such as, rheumatoid arthritis, andosteoarthritis; rheumatoid spondylitis; psoriasis; post ischemicperfusion injury; inflammatory bowel disease; and chronic inflammatorypulmonary disease.

[0111] In one more embodiment still, the invention encompasses methodsof treating, preventing or managing inflammatory disorders in a mammal,comprising administering to a mammal in need thereof, a therapeuticallyeffective amount of a compound of the invention and anotheranti-inflammatory agent.

[0112] In a further embodiment, the invention encompasses a method oftreating, preventing or managing heart disease in a mammal comprisingadministering to said mammal a therapeutically effective amount of acompound of the invention. For example, the compounds of the inventioncan be used to treat, prevent or manage congestive heart failure,cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acuteviral myocarditis, cardiac allograft rejection, and myocardialinfarction.

[0113] In an additional embodiment, the invention encompasses a methodof treating, preventing or managing osteoporosis in a mammal comprisingadministering to said mammal a therapeutically effective amount of acompound of the invention.

[0114] In a further embodiment, the invention encompasses methods oftreating, preventing or managing viral, genetic, allergic, andautoimmune diseases. For example, the compounds are useful to treat,prevent or manage diseases including, but not limited to, HIV,hepatitis, adult respiratory distress syndrome, bone resorptiondiseases, chronic pulmonary inflammatory diseases, dermatitis, cysticfibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock,sepsis syndrome, post ischemic reperfusion injury, meningitis,psoriasis, fibrotic disease, cachexia, graft versus host disease, graftrejection, auto-immune disease, rheumatoid spondylitis, Crohn's disease,ulcerative colitis, inflammatory-bowel disease, multiple sclerosis,systemic lupus erythrematosus, ENL in leprosy, radiation damage, cancer,asthma, or hyperoxic alveolar injury in a mammal comprisingadministering to said mammal a therapeutically effective amount of acompound of the invention.

[0115] In still another embodiment, the invention encompasses a methodof treating, preventing or managing malaria, mycobacterial infection, oran opportunistic infection resulting from HIV in a mammal, comprisingadministering to said mammal a therapeutically effective amount of acompound of the invention.

[0116] In still one more embodiment, the invention relates to treating,preventing or managing mammals having more than one of the conditionstreatable by a compound of the invention.

[0117] In the above embodiments, it is preferable that the mammal be inneed of the treatment or prevention, that is, the mammal is actuallysuffering from a medical condition or at risk of a medical condition forwhich a compound of the invention can provide treatment or prevention.However, the compounds of the invention can also be administered to testanimals that do not necessarily require such treatment or prevention.

[0118] In a further embodiment, the invention encompasses a method ofmodulating the production, preferably inhibiting, or lowering the levelsof PDE4 in a mammalian cell or tissue comprising contacting an effectiveamount of a compound of the invention with said mammalian cell ortissue.

[0119] In a further embodiment, the invention encompasses a method ofmodulating the production or lowering the levels of TNF-α in a mammaliancell or tissue comprising contacting an effective amount of a compoundof the invention with said mammalian cell or tissue.

[0120] In yet another embodiment, the invention encompasses a method ofmodulating the production or lowering the levels of MMP in a mammaliancell or tissue comprising contacting an effective amount of a compoundof the invention with said mammalian cell or tissue.

[0121] In these embodiments, the term “effective amount” means theamount of the compound that will induce the biological response soughtby the researcher, veterinarian, physician, or clinician. It should beunderstood that the cell can be in a cell culture or a tissue culture(in vitro) or in an organism (in vivo) including a human.

[0122] The present invention may be understood by reference to thedetailed description and examples that are intended to exemplifynon-limiting embodiments of the invention.

4.1. Preparation of the Compounds

[0123] The compounds can be prepared using methods which are known ingeneral for the preparation of imides and 2,3-dihydro-1H-isoindolinones.However, the present invention also pertains to an improvement in theformation of the final compounds, as discussed below in greater detail.

[0124] An N-alkoxycarbonylimide and an amine thus are allowed to reactin the presence of a base such as sodium carbonate or sodium bicarbonatesubstantially as described by Shealy et al., Chem. & Ind., (1965)1030-1031) and Shealy et al., J. Pharm. Sci. 57, 757-764 (1968) to yieldthe N-substituted imide. Alternatively, a cyclic acid anhydride can bereacted with an appropriate amine to form an imide. Formation of acyclic imide also can be accomplished by refluxing a solution of anappropriately substituted dicarboxylic acid monoamide in anhydroustetrahydrofuran with N,N′-carbonyldimidazole. Also, a2-bromomethyl-benzoic ester can be reacted with an appropriate amine toform a 2,3-dihydro-1H-isoindolinone as shown below.

[0125] Other methods of formation are described in U.S. Pat. No.5,605,914 and International Publication No. WO 01/34606 A1 which areincorporated herein in there entireties by reference.

4.2. Pharmaceutical Compositions

[0126] This invention provides pharmaceutical compositions comprising apharmaceutically acceptable carrier, excipient or diluent and one ormore compounds of the present invention.

[0127] One embodiment provides the subject compounds combined with apharmaceutically acceptable excipient such as sterile saline,methylcellulose solutions, detergent solutions or other medium, water,gelatin, oils, etc. The compounds or compositions may be administeredalone or in combination with any convenient carrier, diluent, etc., andsuch administration may be provided in single or multiple dosages. Thecompositions are sterile, particularly when used for parenteraldelivery. However, oral unit dosage forms need not be sterile. Usefulcarriers include water soluble and water insoluble solids, fatty acids,micelles, inverse micelles, liposomes and semi-solid or liquid media,including aqueous solutions and non-toxic organic solvents. All of theabove formulations may be treated with ultrasounds, stirred, mixed,high-shear mixed, heated, ground, milled, aerosolized, pulverized,lyophilized, etc., to form pharmaceutically acceptable compositions.

[0128] For preparing pharmaceutical compositions from the compounds ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

[0129] In powders, the carrier is a finely divided solid, which is in amixture with the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

[0130] The powders and tablets preferably contain from 5% or 10% to 70%of the active compound. Suitable carriers are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

[0131] For preparing suppositories, a low melting wax, such as a mixtureof fatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

[0132] Liquid form preparations include solutions, suspensions, andemulsions, for example, water or water/propylene glycol solutions. Forparenteral injection, liquid preparations can be formulated in solutionin aqueous polyethylene glycol solution.

[0133] Aqueous solutions suitable for oral use can be prepared bydissolving the active component in water and adding suitable colorants,flavors, stabilizers, and thickening agents as desired. Aqueoussuspensions suitable for oral use can be made by dispersing the finelydivided active component in water with viscous material, such as naturalor synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

[0134] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

[0135] The pharmaceutical preparation is preferably in unit dosage form.In such form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

[0136] The quantity of active component in a unit dose preparation maybe varied or adjusted from 0.1 mg to 1000 mg, preferably 1.0 mg to 100mg according to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

[0137] The pharmaceutical compositions and methods of the presentinvention may further comprise other therapeutically active compounds,as noted herein, useful in the treatment of metabolic disorders,cardiovascular diseases, inflammatory conditions or neoplastic diseasesand pathologies associated therewith (e.g., diabetic neuropathy) orother adjuvant. In many instances, compositions which include a compoundof the invention and an alternative agent have additive or synergisticeffects when administered.

4.3. Methods of Use

[0138] In accordance with the invention, a compound or composition ofthe invention is administered to a mammal, preferably, a human, with orat risk of a disease or medical condition, for example, cancer, such assolid tumors and blood-born tumors. Specific examples of cancerstreatable, preventable or manageable by administering compounds of theinvention include, but are not limited to, cancers of the skin, such asmelanoma; lymph node; breast; cervix; uterus; gastrointestinal tract;lung; ovary; prostate; colon; rectal; mouth; brain; head and neck;throat; testes; kidney; pancreas; bone; spleen; liver; bladder; larynx;nasal passages; and AIDS-related cancers. The compounds are particularlyuseful for treating cancers of the blood and bone marrow, such asmultiple myeloma and acute and chronic leukemias, for example,lymphoblastic, myelogenous, lymphocytic, and myelocytic leukemias.

[0139] Other specific cancers include, but are not limited to, advancedmalignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma,multiple brain metastase, glioblastoma multiforms, glioblastoma, brainstem glioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C& D colorectal cancer, unresectable colorectal carcinoma, metastatichepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblasticleukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Celllymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, lowgrade follicular lymphoma, metastatic melanoma (localized melanoma,including, but not limited to, ocular melanoma), malignant mesothelioma,malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma,papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma,scelroderma, cutaneous vasculitis, Langerhans cell histiocytosis,leiomyosarcoma, fibrodysplasia ossificans progressive, hormonerefractory prostate cancer, resected high-risk soft tissue sarcoma,unrescectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia,smoldering myeloma, indolent myeloma, fallopian tube cancer, androgenindependent prostate cancer, androgen dependent stage IV non-metastaticprostate cancer, hormone-insensitive prostate cancer,chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma,follicular thyroid carcinoma, medullary thyroid carcinoma, andleiomyoma. In a specific embodiment, the cancer is metastatic. Inanother embodiment, the cancer is refractory or resistance tochemotherapy or radiation; in particular, refractory to thalidomide.

[0140] The compounds of the invention are also useful to treat, preventor manage heart disease, such as congestive heart failure,cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acuteviral myocarditis, cardiac allograft rejection, and myocardialinfarction.

[0141] The compounds of the invention can also be used to treat, preventor manage viral, genetic, inflammatory, allergic, and autoimmunediseases. For example, the compounds are useful to treat, prevent ormanage diseases including, but not limited to, HIV; hepatitis; adultrespiratory distress syndrome; bone-resorption diseases; chronicobstructive pulmonary disease, chronic pulmonary inflammatory diseases;dermatitis; cystic fibrosis; septic shock; sepsis; endotoxic shock;hemodynamic shock; sepsis syndrome; post ischemic reperfusion injury;meningitis; psoriasis; fibrotic disease; cachexia; graft rejection;auto-immune disease; rheumatoid spondylitis; arthritic conditions, suchas rheumatoid arthritis and osteoarthritis; osteoporosis, Crohn'sdisease; ulcerative colitis; inflammatory-bowel disease; multiplesclerosis; systemic lupus erythrematosus; ENL in leprosy; radiationdamage; asthma; and hyperoxic alveolar injury.

[0142] The compounds of the invention are also useful for treating,preventing or managing bacterial infections including, but not limitedto, malaria, mycobacterial infection, and opportunistic infectionsresulting from HIV.

[0143] Another embodiment of the invention encompasses methods oftreating, managing or preventing diseases and disorders associated with,or characterized by, undesired angiogenesis, which compriseadministering to a patient in need of such treatment, management orprevention a therapeutically or prophylactically effective amount of animmunomodulatory compound of the invention, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrugthereof.

[0144] Examples of diseases and disorders associated with, orcharacterized by, undesired angiogenesis include, but are not limitedto, inflammatory diseases, autoimmune diseases, viral diseases, geneticdiseases, allergic diseases, bacterial diseases, ocular neovasculardiseases, choroidal neovascular diseases, retina neovascular diseases,and rubeosis (neovascularization of the angle), which are mediated byundesired or uncontrolled angiogenesis.

[0145] Other examples include, but are not limited to, diabeticretinopathy, retinopathy of prematurity, corneal graft rejection,neovascular glaucoma, retrolental fibroplasia, proliferativevitreoretinopathy, trachoma, myopia, optic pits, epidemickeratoconjunctivitis, atopic keratitis, superior limbic keratitis,pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis,syphilis, lipid degeneration, bacterial ulcer, fungal ulcer, Herpessimplex infection, Herpes zoster infection, protozoan infection, Kaposisarcoma, Mooren ulcer, Terrien's marginal degeneration, mariginalkeratolysis, rheumatoid arthritis, systemic lupus, polyarteritis,trauma, Wegeners sarcoidosis, scleritis, Steven's Johnson disease,periphigoid radial keratotomy, sickle cell anemia, sarcoid,pseudoxanthoma elasticum, Pagets disease, vein occlusion, arteryocclusion, carotid obstructive disease, chronic uveitis, chronicvitritis, Lyme's disease, Eales disease, Bechet's disease, retinitis,choroiditis, presumed ocular histoplasmosis, Bests disease, Stargartsdisease, pars planitis, chronic retinal detachment, hyperviscositysyndromes, toxoplasmosis, rubeosis, sarcodisis, sclerosis, soriatis,psoriasis, primary sclerosing cholangitis, proctitis, primary biliarysrosis, idiopathic pulmonary fibrosis, alcoholic hepatitis, endotoxemia,toxic shock syndrome, osteoarthritis, retrovirus replication, wasting,meningitis, silica-induced fibrosis, asbestos-induced fibrosis,malignancy-associated hypercalcemia, stroke, circulatory shock,periodontitis, gingivitis, macrocytic anemia, refractory anemia,5q-syndrome, and veterinary disorder caused by feline immunodeficiencyvirus, equine infectious anemia virus, caprine arthritis virus, visnavirus, maedi virus or lenti virus.

[0146] In certain embodiment of the invention, specific diseases do notinclude congestive heart failure, cardiomyopathy, pulmonary edema,endotoxin-mediated septic shock, acute viral myocarditis, cardiacallograft rejection, myocardial infarction, HIV, hepatitis, adultrespiratory distress syndrome, bone-resorption disease, chronicobstructive pulmonary diseases, chronic pulmonary inflammatory disease,dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock,hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury,meningitis, psoriasis, fibrotic disease, cachexia, graft rejection,rheumatoid spondylitis, osteoporosis, Crohn's disease, ulcerativecolitis, inflammatory-bowel disease, multiple sclerosis, systemic lupuserythrematosus, erythema nodosum leprosum in leprosy, radiation damage,asthma, hyperoxic alveolar injury, malaria and mycobacterial infection.

[0147] The compounds of the invention are also useful for preventingheart disease, such as congestive heart failure, cardiomyopathy,pulmonary edema, endotoxin-mediated septic shock, acute viralmyocarditis, cardiac allograft rejection, and myocardial infarction.

[0148] The compounds of the invention are also useful for treating,preventing or managing MDS and related syndromes, such as, but notlimited to, refractory anemia (RA), RA with ringed sideroblasts (RARS),RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), chronicmyelomonocytic leukemia (CMML), and symptoms such as anemia,thrombocytopenia, neutropenia, cytopenias, bicytopenia (two deficientcell lines), and pancytopenia (three deficient cell lines).

[0149] The compounds of the invention are also useful for treating,preventing or managing CRPS and related syndromes. As used herein, andunless otherwise specified, the term “CRPS” refers to a chronic paindisorder characterized by one or more of the following: pain, whetherspontaneous or evoked, including allodynia (painful response to astimulus that is not usually painful) and hyperalgesia (exaggeratedresponse to a stimulus that is usually only mildly painfull); pain thatis disproportionate to the inciting event (e.g., years of severe painafter an ankle sprain); regional pain that is not limited to a singleperipheral nerve distribution; and autonomic dysregulation (e.g., edema,alteration in blood flow and hyperhidrosis) associated with trophic skinchanges (hair and nail growth abnormalities and cutaneous ulceration).Unless otherwise indicated, the terms “complex regional pain syndrome,”“CRPS” and “CRPS and related syndromes” include: type I, encompassingthe condition known as reflex sympathetic dystrophy (RSD), which occursafter an initial noxious event other than a nerve injury; type II,encompassing the condition known as causalgia, which occurs after nerveinjury; acute stage (usually hyperthermic phase of 2-3 months);dystrophic phase (showing vasomotor instability for several months);atrophic phase (usually cold extremity with atrophic changes); reflexneurovascular dystrophy; reflex dystrophy; sympathetic maintained painsyndrome; Sudeck atrophy of bone; algoneurodystrophy; shoulder handsyndrome; post-traumatic dystrophy; trigeminal neuralgia; post herpeticneuralgia; cancer related pain; phantom limb pain; fibromyalgia; chronicfatigue syndrome; radiculopathy; and other painful neuropathicconditions, e.g., diabetic neuropathy, luetic neuropathy, or painfulneuropathic condition iatrogenically induced from drugs such asvincristine, velcade and thalidomide.

[0150] The compounds of the invention are useful for treating,preventing or managing all types of CRPS and related syndromes,including, but not limited to, those referred to as CRPS type I, CRPStype II, reflex sympathetic dystrophy (RSD), reflex neurovasculardystrophy, reflex dystrophy, sympathetically maintained pain syndrome,causalgia, Sudeck atrophy of bone, algoneurodystrophy, shoulder handsyndrome, post-traumatic dystrophy, trigeminal neuralgia, post herpeticneuralgia, cancer related pain, phantom limb pain, fibromyalgia, chronicfatigue syndrome, post-operative pain, spinal cord injury pain, centralpost-stroke pain, radiculopathy, and other painful neuropathicconditions, e.g., diabetic neuropathy.

[0151] The compounds of the invention are also useful for treating,preventing and managing MD and related syndromes, such as, but notlimited to, atrophic (dry) MD, exudative (wet) MD, age-relatedmaculopathy (ARM), choroidal neovascularisation (CNVM), retinal pigmentepithelium detachment (PED), and atrophy of retinal pigment epithelium(RPE).

[0152] As used herein, the term macular degeneration (MD) encompassesall forms of macular degenerative diseases regardless of a patient'sage, although some macular degenerative diseases are more common incertain age groups. These include, but are not limited to, Best'sdisease or vitelliform (most common in patients under about 7 years ofage); Stargardt's disease, juvenile macular dystrophy or fundusflavimaculatus (most common in patients between about 5 and about 20years of age); Behr's disease, Sorsby's disease, Doyne's disease orhoneycomb dystrophy (most common in patients between about 30 and about50 years of age); and age-related macular degeneration (most common inpatients of about 60 years of age or older).

[0153] Symptoms associated with MD and related syndromes include, butare not limited to, drusen rounded whitish-yellowish spots in thefludus, submacular disciform scar tissue, choroidal neovascularisation,retinal pigment epithelium detachment, atrophy of retinal pigmentepithelium, abnormal blood vessels stemming from the choroid (the bloodvessel-rich tissue layer just beneath the retina), a blurry or distortedarea of vision, a central blind spot, pigmentary abnormalities, acontinuous layer of fine granular material deposited in the inner partof Bruch's membrane, and a thickening and decreased permeability ofBruch's membrane.

[0154] Causes of MD include, but are not limited to, genetic, physicaltrauma, diseases such as diabetes, and infection, such as bacterialinfection (e.g., leprosy and ENL in particular). The compounds of theinvention can effectively treat, prevent or manage all types of MD andrelated syndromes or symptoms, regardless of their causes.

[0155] The compounds of the invention are also useful for treating,preventing or managing all types of MPD and related syndromes orsymptoms. Examples of MPD that can be treated, prevented or managed bythe compounds of the invention include, but are not limited to,polycythemia rubra vera (PRV), primary thromobocythemia (PT), chronicmyelogenous leukemia (CML), and agnogenic myeloid metaplasia (AMM).

[0156] As used herein, the term “myeloproliferative disease,” or “MPD,”means a hematopoietic stem cell disorder characterized by one or more ofthe following: clonal expansion of a multipotent hematopoieticprogenitor cell with the overproduction of one or more of the formedelements of the blood (e.g., elevated red blood cell count, elevatedwhite blood cell count, and/or elevated platelet count), presence ofPhiladelphia chromosome or bcr-abl gene, teardrop poikilocytosis onperipheral blood smear, leukoerythroblastic blood pictuer, giantabnormal platelets, hypercellular bone marrow with reticular or collagenfibrosis, marked left-shifted myeloid series with a low percentage ofpromyelocytes and blasts, splenomegaly, thrombosis, risk of progressionto acute leukemia or cellular marrow with impaired morphology. The term“myeloproliferative disease,” or “MPD,” unless otherwise noted,includes: polycythemia rubra vera (PRV), primary thromobocythemia (PT),chronic myelogenous leukemia (CML), and agnogenic myeloid metaplasia(AMM).

[0157] Symptoms associated with MPD include, but are not limited to,headache, dizziness, tinnitus, blurred vision, fatigue, night sweat,low-grade fever, generalized pruritus, epistaxis, blurred vision,splenomegaly, abdominal fullness, thrombosis, increased bleeding,anemia, splenic infarction, severe bone pain, hematopoiesis in theliver, ascites, esophageal varices, liver failure, respiratory distress,and priapism. Laboratory findings associated with MPD include, but arenot limited to, clonal expansion of a multipotent hematopoieticprogenitor cell with the overproduction of one or more of the formedelements of the blood (e.g., elevated red blood cell count, elevatedwhite blood cell count, and/or elevated platelet count), presence ofPhiladelphia chromosome or bcr-abl gene, teardrop poikilocytosis onperipheral blood smear, leukoerythroblastic blood pictuer, giantabnormal platelets, hypercellular bone marrow with reticular or collagenfibrosis, and marked left-shifted myeloid series with a low percentageof promyelocytes and blasts.

[0158] The compounds of the invention are also useful for treating,preventing and managing all tyoes of CNS disorders. Examples of CNSdisorders include, but are not limited to, Parkinson disease; Alzheimerdisease, mild cognitive impairment; depression; defective long-termmemory; Amyotrophic Lateral Sclerosis (ALS); CNS trauma; hypokineticdisorders; bradykinesia; slowness of movement; paucity of movement;impairment of dexterity; hypophonia; monotonic speech; muscularrigidity; masked faces; decreased blinking; stooped posture; decreasedarm swinging when walking; micrographia; parkinsonian tremor;parkinsonian gait; postural instability; festinating gait; motionfreezing; disturbances of cognition, mood, sensation, sleep or autonomicfunction; dementia; and sleep disorders.

[0159] In a specific embodiment, the central nervous system disorder tobe prevented, treated and/or managed is Parkinson disease, Alzheimerdisease, mild cognitive impairment, dementia, depression, defectivelong-term memory, Amyotrophic Lateral Sclerosis (ALS) or CNS trauma.

[0160] The invention encompasses methods of treating, preventing ormanaging central nervous system disorders, preferably Parkinson diseaseor Alzheimer disease. In one embodiment, the methods of the inventionare used to treat, prevent or manage disorders related to movement,including, but not limited to, slow execution or bradykinesia, paucityof movement or akinesia, movement disorders that impair fine motorcontrol and finger dexterity, and other manifestations of bradykinesia,such as, but not limited to, hypophonia and monotonic speech. In anotherembodiment, the methods of the invention are used to treat, prevent ormanage disorders related to muscular rigidity, including, but notlimited to, a uniform increase in resistance to passive movement,interruptions to passive movement, and combinations of rigidity anddystonia. In a specific embodiment, methods of the invention are used totreat inflammation associated with Parkinson or related disease. In yetanother embodiment of the invention, disorders resembling Parkinsoniantremor are treated, prevented or managed by the methods of theinvention, including but not limited to, tremors of the face, jaw,tongue, posture, and other tremors that are present at rest and thatattenuate during movement. In another embodiment, the methods of theinvention are used to treat, prevent or manage disorders in gait,including, but not limited to, those resembling parkinsonian gait,shuffling, short steps, a tendency to turn en bloc, and festinatinggait. In another embodiment of the invention, nonmotor symptoms aretreated, prevented or managed using the methods of the invention,including, but not limited to, disorders of mood, cognition, defectivelong-term memory, sensation, sleep, dementia, and depression. In otherembodiment of the invention, secondary forms of parkinsonism aretreated, prevented or managed by the methods of the invention,including, but not limited to, drug induced parkinsonism, vascularparkinsonism, multiple system atrophy, progressive supranuclear palsy,disorders with primary tau pathology, cortical basal gangliadegeneration, parkinsonism with dementia, hyperkinetic disorders,chorea, Huntington disease, dystonia, Wilson disease, Tourette syndrome,essential tremor, myoclonus, and tardive movement disorders. In otherembodiment of the invention, other central nervous system disorders aretreated, prevented or managed by the methods of the invention,including, but not limited to, Alzheimer disease, mild cognitiveimpairment, Amyotrophic Lateral Sclerosis (ALS) and CNS trauma.

[0161] The compounds of the invention are also useful for treating,preventing or managing an asbestos-related disease or disorder andrelated symptoms. Examples of asbestos-related diseases or disordersinclude, but are not limited to, malignant mesothelioma, asbestosis,malignant pleural effusion, benign pleural effusion, pleural plaque,pleural calcification, diffuse pleural thickening, round atelectasis,and bronchogenic carcinoma. It further encompasses methods of treatingpatients who have been previously treated for asbestos-related diseasesor disorders but were not sufficiently responsive or werenon-responsive, as well as those who have not previously been treatedfor the diseases or disorders. Because patients have heterogenousclinical manifestations and varying clinical outcomes, the treatmentgiven to a patient may vary, depending on his/her prognosis. The skilledclinician will be able to readily determine without undueexperimentation specific secondary agents and types of physical therapythat can be effectively used to treat an individual patient.

[0162] Symptoms of asbestos-related diseases or disorders include, butare not limited to, dyspnea, obliteration of the diaphragm, radiolucentsheet-like encasement of the pleura, pleural effusion, pleuralthickening, decreased size of the chest, chest discomfort, chest pain,easy fatigability, fever, sweats and weight loss. Examples of patientsat risk of asbestos-related diseases or disorders include, but are notlimited to, those who have been exposed to asbestos in the workplace andtheir family members who have been exposed to asbestos embedded in theworker's clothing. Patients having familial history of asbestos-relateddiseases or disorders are also preferred candidates for preventiveregimens.

4.4. Pharmaceutical Formulations

[0163] Administration of compounds of the invention can be systemic orlocal. In most instances, administration to a mammal will result insystemic release of the compounds of the invention (i.e., into thebloodstream). Methods of administration include enteral routes, such asoral, buccal, sublingual, and rectal; topical administration, such astransdermal and intradermal; and parenteral administration. Suitableparenteral routes include injection via a hypodermic needle or catheter,for example, intravenous, intramuscular, subcutaneous, intradermal,intraperitoneal, intraarterial, intraventricular, intrathecal, andintracameral injection and non-injection routes, such as intravaginalrectal, or nasal administration. Preferably, the compounds andcompositions of the invention are administered orally. In specificembodiments, it may be desirable to administer one or more compounds ofthe invention locally to the area in need of treatment. This may beachieved, for example, by local infusion during surgery, topicalapplication, e.g., in conjunction with a wound dressing after surgery,by injection, by means of a catheter, by means of a suppository, or bymeans of an implant, said implant being of a porous, non-porous, orgelatinous material, including membranes, such as sialastic membranes,or fibers.

[0164] The compounds of the invention can be administered via typical aswell as non-standard delivery systems, e.g., encapsulation in liposomes,microparticles, microcapsules, capsules, etc. For example, the compoundsand compositions of the invention can be delivered in a vesicle, inparticular a liposome (see Langer, 1990, Science 249:1527-1533; Treat etal., in Liposomes in Therapy of Infectious Disease and Cancer,Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989);Lopez-Berestein, ibid., pp. 317-327; see generally ibid.). In anotherexample, the compounds and compositions of the invention can bedelivered in a controlled release system. In one embodiment, a pump maybe used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng.14:201; Buchwald et al., 1980, Surgery 88:507 Saudek et al., 1989, N.Engl. J. Med. 321:574). In another example, polymeric materials can beused (see Medical Applications of Controlled Release, Langer and Wise(eds.), CRC Press., Boca Raton, Fla. (1974); Controlled DrugBioavailability, Drug Product Design and Performance, Smolen and Ball(eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol.Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989,J. Neurosurg. 71:105). In still another example, a controlled-releasesystem can be placed in proximity of the target area to be treated,e.g., the liver, thus requiring only a fraction of the systemic dose(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systemsdiscussed in the review by Langer, 1990, Science 249:1527-1533) can beused.

[0165] When administered as a composition, a compound of the inventionwill be formulated with a suitable amount of a pharmaceuticallyacceptable vehicle or carrier so as to provide the form for properadministration to the mammal. The term “pharmaceutically acceptable”means approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in mammals, and more particularly inhumans. The term “vehicle” refers to a diluent, adjuvant, excipient, orcarrier with which a compound of the invention is formulated foradministration to a mammal. Such pharmaceutical vehicles can be liquids,such as water and oils, including those of petroleum, animal, vegetableor synthetic origin, such as peanut oil, soybean oil, mineral oil,sesame oil and the like. The pharmaceutical vehicles can be saline, gumacacia, gelatin, starch paste, talc, keratin, colloidal silica, urea,and the like. In addition, auxiliary, stabilizing, thickening,lubricating and coloring agents may be used. Preferably, whenadministered to a mammal, the compounds and compositions of theinvention and pharmaceutically acceptable vehicles, excipients, ordiluents are sterile. An aqueous medium is a preferred vehicle when thecompound of the invention is administered intravenously, such as water,saline solutions, and aqueous dextrose and glycerol solutions.

[0166] The present compounds and compositions can take the form ofcapsules, tablets, pills, pellets, lozenges, powders, granules, syrups,elixirs, solutions, suspensions, emulsions, suppositories, orsustained-release formulations thereof, or any other form suitable foradministration to a mammal. In a preferred embodiment, the compounds andcompositions of the invention are formulated for administration inaccordance with routine procedures as a pharmaceutical compositionadapted for oral or intravenous administration to humans. In oneembodiment, the pharmaceutically acceptable vehicle is a hard gelatincapsule. Examples of suitable pharmaceutical vehicles and methods forformulation thereof are described in Remington: The Science and Practiceof Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa.,19th ed., 1995, Chapters 86, 87, 88, 91, and 92, incorporated herein byreference.

[0167] Compounds and compositions of the invention formulated for oraldelivery, are preferably in the form of capsules, tablets, pills, or anycompressed pharmaceutical form. Moreover, where in tablet or pill form,the compounds and compositions may be coated to delay disintegration andabsorption in the gastrointestinal tract thereby providing a sustainedaction over an extended period of time. Selectively permeable membranessurrounding an osmotically active driving compound are also suitable fororally administered compounds and compositions of the invention. Inthese later platforms, fluid from the environment surrounding thecapsule is imbibed by the driving compound that swells to displace theagent or agent composition through an aperture. These delivery platformscan provide an essentially zero order delivery profile as opposed to thespiked profiles of immediate release formulations. A time delay materialsuch as glycerol monostearate or glycerol stearate may also be used.Oral compositions can include standard vehicles, excipients, anddiluents, such as magnesium stearate, sodium saccharine, cellulose,magnesium carbonate, lactose, dextrose, sucrose, sorbitol, mannitol,starch, gum acacia, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidinone, water, syrup, and methyl cellulose, theformulations can additionally include lubricating agents, such as talc,magnesium stearate, mineral oil, wetting agents, emulsifying andsuspending agents, preserving agents such as methyl- andpropylhydroxybenzoates. Such vehicles are preferably of pharmaceuticalgrade. Orally administered compounds and compositions of the inventioncan optionally include one or more sweetening agents, such as fructose,aspartame or saccharin; one or more flavoring agents such as peppermint,oil of wintergreen, or cherry; or one or more coloring agents to providea pharmaceutically palatable preparation.

[0168] A therapeutically effective dosage regimen for the treatment of aparticular disorder or condition will depend on its nature and severity,and can be determined by standard clinical techniques according to thejudgment of a medical practitioner. In addition, in vitro or in vivoassays can be used to help identify optimal dosages. Of course, theamount of a compound of the invention that constitutes a therapeuticallyeffective dose also depends on the administration route. In general,suitable dosage ranges for oral administration are about 0.001milligrams to about 20 milligrams of a compound of the invention perkilogram body weight per day, preferably, about 0.7 milligrams to about6 milligrams, more preferably, about 1.5 milligrams to about 4.5milligrams. In a preferred embodiment, a mammal, preferably, a human isorally administered about 0.01 mg to about 1000 mg of a compound of theinvention per day, more preferably, about 0.1 mg to about 300 mg perday, or about 1 mg to about 100 mg in single or divided doses. Thedosage amounts described herein refer to total amounts administered;that is, if more than one compound of the invention is administered, thepreferred dosages correspond to the total amount of the compounds of theinvention administered. Oral compositions preferably contain 10% to 95%of a compound of the invention by weight. Preferred unit oral-dosageforms include pills, tablets, and capsules, more preferably capsules.Typically such unit-dosage forms will contain about 0.01 mg, 0.1 mg, 1mg, 5 mg, 10 mg, 15 mg, 20 mg, 50 mg, 100 mg, 250 mg, or 500 mg of acompound of the invention, preferably, from about 5 mg to about 200 mgof compound per unit dosage.

[0169] In another embodiment, the compounds and compositions of theinvention can be administered parenterally (e.g., by intramuscular,intrathecal, intravenous, and intraarterial routes), preferably,intravenously. Typically, compounds and compositions of the inventionfor intravenous administration are solutions in sterile isotonic aqueousvehicles, such as water, saline, Ringer's solution, or dextrosesolution. Where necessary, the compositions may also include asolubilizing agent. Compositions for intravenous administration mayoptionally include a local anesthetic such as lignocaine to ease pain atthe site of the injection. For intravenous administration, the compoundsand compositions of the invention can be supplied as a sterile, drylyophilized powder or water-free concentrate in a hermetically sealedcontainer, such as an ampule or sachette, the container indicating thequantity of active agent. Such a powder or concentrate is then dilutedwith an appropriate aqueous medium prior to intravenous administration.An ampule of sterile water, saline solution, or other appropriateaqueous medium can be provided with the powder or concentrate fordilution prior to administration. Or the compositions can be supplied inpre-mixed form, ready for administration. Where a compound orcomposition of the invention is to be administered by intravenousinfusion, it can be dispensed, for example, with an infusion bottlecontaining sterile pharmaceutical-grade water, saline, or other suitablemedium.

[0170] Rectal administration can be effected through the use ofsuppositories formulated from conventional carriers such as cocoabutter, modified vegetable oils, and other fatty bases. Suppositoriescan be formulated by well-known methods using well-known formulations,for example see Remington: The Science and Practice of Pharmacy, AlfonsoR. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995, pp.1591-1597, incorporated herein by reference

[0171] To formulate and administer topical dosage forms, well-knowntransdermal and intradermal delivery mediums such as lotions, creams,and ointments and transdermal delivery devices such as patches can beused (Ghosh, T. K.; Pfister, W. R.; Yum, S. I. Transdermal and TopicalDrug Delivery Systems, Interpharm Press, Inc. p. 249-297, incorporatedherein by reference). For example, a reservoir type patch design cancomprise a backing film coated with an adhesive, and a reservoircompartment comprising a compound or composition of the invention, thatis separated from the skin by a semipermeable membrane (e.g., U.S. Pat.No. 4,615,699, incorporated herein by reference). The adhesive coatedbacking layer extends around the reservoir's boundaries to provide aconcentric seal with the skin and hold the reservoir adjacent to theskin.

[0172] Mucosal dosage forms of the invention include, but are notlimited to, ophthalmic solutions, sprays and aerosols, or other formsknown to one of skill in the art. See, e.g., Remington's PharmaceuticalSciences, 18th eds., Mack Publishing, Easton Pa. (1990); andIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.In one embodiment, the aerosol comprises a carrier. In anotherembodiment, the aerosol is carrier free.

[0173] The compounds of the invention may also be administered directlyto the lung by inhalation. For administration by inhalation, a compoundof the invention can be conveniently delivered to the lung by a numberof different devices. For example, a Metered Dose Inhaler (“MDI”) whichutilizes canisters that contain a suitable low boiling propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas can beused to deliver a compound of formula I directly to the lung. MDIdevices are available from a number of suppliers such as 3M Corporation,Aventis, Boehringer Ingleheim, Forest Laboratories, Glaxo-Wellcome,Schering Plough and Vectura.

[0174] Alternatively, a Dry Powder Inhaler (DPI) device can be used toadminister a compound of the invention to the lung (See, e.g., Raleighet al., Proc. Amer. Assoc. Cancer Research Annual Meeting, 1999, 40,397, which is herein incorporated by reference). DPI devices typicallyuse a mechanism such as a burst of gas to create a cloud of dry powderinside a container, which can then be inhaled by the patient. DPIdevices are also well known in the art and can be purchased from anumber of vendors which include, for example, Fisons, Glaxo-Wellcome,Inhale Therapeutic Systems, ML Laboratories, Qdose and Vectura. Apopular variation is the multiple dose DPI (“MDDPI”) system, whichallows for the delivery of more than one therapeutic dose. MDDPI devicesare available from companies such as AstraZeneca, Glaxo Wellcome, IVAX,Schering Plough, SkyePharma and Vectura. For example, capsules andcartridges of gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch for these systems.

[0175] Another type of device that can be used to deliver a compound ofthe invention to the lung is a liquid spray device supplied, forexample, by Aradigm Corporation. Liquid spray systems use extremelysmall nozzle holes to aerosolize liquid drug formulations that can thenbe directly inhaled into the lung.

[0176] In a preferred embodiment, a nebulizer device is used to delivera compound of the invention to the lung. Nebulizers create aerosols fromliquid drug formulations by using, for example, ultrasonic energy toform fine particles that can be readily inhaled (See e.g., Verschoyle etal., British J. Cancer, 1999, 80, Suppl 2, 96, which is hereinincorporated by reference). Examples of nebulizers include devicessupplied by Sheffield/Systemic Pulmonary Delivery Ltd. (See, Armer etal., U.S. Pat. No. 5,954,047; van der Linden et al., U.S. Pat. No.5,950,619; van der Linden et al., U.S. Pat. No. 5,970,974, which areherein incorporated by reference), Aventis and Batelle PulmonaryTherapeutics

[0177] In a particularly preferred embodiment, an electrohydrodynamic(“EHD”) aerosol device is used to deliver a compound of the invention tothe lung. EHD aerosol devices use electrical energy to aerosolize liquiddrug solutions or suspensions (see e.g., Noakes et al., U.S. Pat. No.4,765,539; Coffee, U.S. Pat. No. 4,962,885; Coffee, PCT Application, WO94/12285; Coffee, PCT Application, WO 94/14543; Coffee, PCT Application,WO 95/26234, Coffee, PCT Application, WO 95/26235, Coffee, PCTApplication, WO 95/32807, which are herein incorporated by reference).The electrochemical properties of the compound of formula I formulationmay be important parameters to optimize when delivering this drug to thelung with an EHD aerosol device and such optimization is routinelyperformed by one of skill in the art. EHD aerosol devices may moreefficiently delivery drugs to the lung than existing pulmonary deliverytechnologies. Other methods of intra-pulmonary delivery will be known tothe skilled artisan and are within the scope of the invention.

[0178] Liquid drug formulations suitable for use with nebulizers andliquid spray devices and EHD aerosol devices will typically apharmaceutically acceptable carrier. Preferably, the pharmaceuticallyacceptable carrier is a liquid such as alcohol, water, polyethyleneglycol or a perfluorocarbon. Optionally, another material may be addedto alter the aerosol properties of the solution or suspension of acompound of the invention. Preferably, this material is liquid such asan alcohol, glycol, polyglycol or a fatty acid. Other methods offormulating liquid drug solutions or suspension suitable for use inaerosol devices are known to those of skill in the art (See, e.g.,Biesalski, U.S. Pat. Nos. 5,112,598; Biesalski, 5,556,611, which areherein incorporated by reference) A compound of formula I can also beformulated in rectal or vaginal compositions such as suppositories orretention enemas, e.g., containing conventional suppository bases suchas cocoa butter or other glycerides.

[0179] In addition to the formulations described previously, a compoundof the invention can also be formulated as a depot preparation. Suchlong acting formulations can be administered by implantation (forexample subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds can be formulated withsuitable polymeric or hydrophobic materials (for example, as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

[0180] Alternatively, other pharmaceutical delivery systems can beemployed. Liposomes and emulsions are well known examples of deliveryvehicles that can be used to deliver compounds of the inventions.Certain organic solvents such as dimethylsulfoxide can also be employed,although usually at the cost of greater toxicity. A compound of theinvention can also be delivered in a controlled release system. In oneembodiment, a pump can be used (Sefton, CRC Crit. Ref Biomed Eng., 1987,14, 201; Buchwald et al., Surgery, 1980, 88, 507; Saudek et al., N.Engl. J Med, 1989, 321, 574). In another embodiment, polymeric materialscan be used (see Medical Applications of Controlled Release, Langer andWise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled DrugBioavailability, Drug Product Design and Performance, Smolen and Ball(eds.), Wiley, New York (1984); Ranger and Peppas, J Macromol. Sci. Rev.Macromol. Chem., 1983, 23, 61; see also Levy et al., Science 1985, 228,190; During et al., Ann. Neurol., 1989, 25, 351; Howard et al., 1989, J.Neurosurg. 71, 105). In yet another embodiment, a controlled-releasesystem can be placed in proximity of the target of the compounds of theinvention, e.g., the lung, thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, in Medical Applications of ControlledRelease, supra, vol. 2, pp. 115 (1984)). Other controlled-release systemcan be used (see e.g. Langer, Science, 1990, 249, 1527).

[0181] Suitable excipients (e.g., carriers and diluents) and othermaterials that can be used to provide mucosal dosage forms encompassedby this invention are well known to those skilled in the pharmaceuticalarts, and depend on the particular site or method which a givenpharmaceutical composition or dosage form will be administered. Withthat fact in mind, typical excipients include, but are not limited to,water, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol,isopropyl myristate, isopropyl palmitate, mineral oil, and mixturesthereof, which are non-toxic and pharmaceutically acceptable. Examplesof such additional ingredients are well known in the art. See, e.g.,Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, EastonPa. (1990).

[0182] The pH of a pharmaceutical composition or dosage form, or of thetissue to which the pharmaceutical composition or dosage form isapplied, can also be adjusted to improve delivery of one or more activeingredients. Similarly, the polarity of a solvent carrier, its ionicstrength, or tonicity can be adjusted to improve delivery. Compoundssuch as stearates can also be added to pharmaceutical compositions ordosage forms to advantageously alter the hydrophilicity or lipophilicityof one or more active ingredients so as to improve delivery. In thisregard, stearates can serve as a lipid vehicle for the formulation, asan emulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

[0183] The invention also provides pharmaceutical packs or kitscomprising one or more containers filled with one or more compounds ofthe invention. Optionally associated with such container(s) can be anotice in the form prescribed by a governmental agency regulating themanufacture, use or sale of pharmaceuticals or biological products,which notice reflects approval by the agency of manufacture, use or salefor human administration. In one embodiment, the kit contains more thanone compound of the invention. In another embodiment, the kit comprisesa compound of the invention and another biologically active agent.

[0184] The compounds of the invention are preferably assayed in vitroand in vivo, for the desired therapeutic or prophylactic activity, priorto use in humans. For example, in vitro assays can be used to determinewhether administration of a specific compound of the invention or acombination of compounds of the invention is preferred. The compoundsand compositions of the invention may also be demonstrated to beeffective and safe using animal model systems. Other methods will beknown to the skilled artisan and are within the scope of the invention.

4.5. Combination Therapy

[0185] In certain embodiments, a compound of the invention isadministered to a mammal, preferably, a human concurrently with one ormore other therapeutic agents, or with one or more other compounds ofthe invention, or with both. By “concurrently” it is meant that acompound of the invention and the other agent are administered to amammal in a sequence and within a time interval such that the compoundof the invention can act together with the other agent to provide anincreased or synergistic benefit than if they were administeredotherwise. For example, each component may be administered at the sametime or sequentially in any order at different points in time; however,if not administered at the same time, they should be administeredsufficiently closely in time so as to provide the desired treatmenteffect. Preferably, all components are administered at the same time,and if not administered at the same time, preferably, they are alladministered from about 6 hours to about 12 hours apart from oneanother.

[0186] When used in combination with other therapeutic agents, thecompounds of the invention and the therapeutic agent can act additivelyor, more preferably, synergistically. In one embodiment, a compound or acomposition of the invention is administered concurrently with anothertherapeutic agent in the same pharmaceutical composition. In anotherembodiment, a compound or a composition of the invention is administeredconcurrently with another therapeutic agent in separate pharmaceuticalcompositions. In still another embodiment, a compound or a compositionof the invention is administered prior or subsequent to administrationof another therapeutic agent. As many of the disorders for which thecompounds and compositions of the invention are useful in treating arechronic disorders, in one embodiment combination therapy involvesalternating between administering a compound or a composition of theinvention and a pharmaceutical composition comprising anothertherapeutic agent, e.g., to minimize the toxicity associated with aparticular drug. In certain embodiments, when a composition of theinvention is administered concurrently with another therapeutic agentthat potentially produces adverse side effects including, but notlimited to toxicity, the therapeutic agent can advantageously beadministered at a dose that falls below the threshold that the adverseside effect is elicited. Additional therapeutic agents include, but arenot limited to, hematopoietic growth factors, cytokines, anti-canceragents, antibiotics, immunosuppressive agents, steroids, antihistamines,lukatriene inhibitors and other therapeutics discussed herein.

[0187] Preferred additional therapeutic agents include, but are notlimited to, Remicade™, docetaxel, Celecoxib™, melphalan, dexamethasone,steroids, gemcitabine, cisplatinum, temozolomide, etoposide,cyclophosphamide, temodar, carboplatin, procarbazine, gliadel,tamoxifen, topotecan, methotrexate, Arisa®, Taxol™, taxotere,fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha,pegylated interferon alpha, capecitabine, cisplatin, thiotepa,fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol,pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine,zoledronic acid, palmitronate, biaxin, busulphan, prednisone,bisphosphonate, arsenic trioxide, PEG INTRON-A, doxil, vincristine,decadron, doxorubicin, paclitaxel, ganciclovir, adriamycin,estramustine, Emcyt, sulindac, and etoposide.

[0188] The invention further encompasses mutants and derivatives (e.g.,modified forms) of naturally occurring proteins that exhibit, in vivo,at least some of the pharmacological activity of the proteins upon whichthey are based. Examples of mutants include, but are not limited to,proteins that have one or more amino acid residues that differ from thecorresponding residues in the naturally occurring forms of the proteins.Also encompassed by the term “mutants” are proteins that lackcarbohydrate moieties normally present in their naturally occurringforms (e.g., nonglycosylated forms). Examples of derivatives include,but are not limited to, pegylated derivatives and fusion proteins, suchas proteins formed by fusing IgG1 or IgG3 to the protein or activeportion of the protein of interest. See, e.g., Penichet, M. L. andMorrison, S. L., J. Immunol. Methods 248:91-101 (2001).

[0189] Recombinant and mutated forms of G-CSF can be prepared asdescribed in U.S. Pat. Nos. 4,810,643; 4,999,291; 5,528,823; and5,580,755; all of which are incorporated herein by reference.Recombinant and mutated forms of GM-CSF can be prepared as described inU.S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496; all of which areincorporated herein by reference. In fact, recombinant forms of G-CSFand GM-CSF are currently sold in the United States for the treatment ofsymptoms associated with specific chemotherapies. A recombinant form ofG-CSF known as filgrastim is sold in the United States under the tradename NEUPOGEN®, and is indicated to decrease the incidence of infection,as manifested by febrile neutropenia, in patients with nonmyeloidmalignancies receiving myelosuppressive anti-cancer drugs associatedwith a significant incidence of severe neutropenia with fever.Physicians' Desk Reference, 587-592 (56^(th) ed., 2002). A recombinantform of GM-CSF known as sargramostim is also sold in the United Statesunder the trade name LEUKINE®. LEUKINE® is indicated for use followinginduction chemotherapy in older adult patients with acute myelogenousleukemia (AML) to shorten time to neutrophil recovery. Physicians' DeskReference, 1755-1760 (56^(th) ed., 2002). A recombinant form of EPOknown as epoetin alfa is sold in the United States under the trade nameEPOGEN®. EPOGEN® is used to stimulate red cell production by stimulatingdivision and maturation of committed red cell precursor cells.Physicians' Desk Reference, 582-587 (56^(th) ed., 2002).

[0190] A growth-factor or cytokine such as G-CSF, GM-CSF and EPO canalso be administered in the form of a vaccine. For example, vaccinesthat secrete, or cause the secretion of, cytokines such as G-CSF andGM-CSF can be used in the methods, pharmaceutical compositions, and kitsof the invention. See, e.g., Emens, L. A., et al., Curr. Opinion Mol.Ther. 3(1):77-84 (2001).

[0191] Examples of anti-cancer drugs that can be used in the variousembodiments of the invention, including the methods, dosing regimens,cocktails, pharmaceutical compositions and dosage forms and kits of theinvention, include, but are not limited to: acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; dacarbazine; docetaxel; doxorubicin; doxorubicinhydrochloride; droloxifene; droloxifene citrate; dromostanolonepropionate; duazomycin; edatrexate; eflomithine hydrochloride;elsamitrucin; enloplatin; enpromate; epipropidine; epirubicinhydrochloride; erbulozole; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide; etoposidephosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide;floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;interleukin II (including recombinant interleukin II, or rIL2),interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferonalfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin;irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole;leuprolide acetate; liarozole hydrochloride; lometrexol sodium;lomustine; losoxantrone hydrochloride; masoprocol; maytansine;mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium;metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran;paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride. Other anti-cancer drugs include, but are not limited to:20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole;cartilage derived inhibitor; carzelesin; casein kinase inhibitors(ICOS); castanospemine; cecropin B; cetrorelix; chlorlns;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol; dioxamycin; diphenyl spiromustine; docetaxel; docosanol;dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol;duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;eflornithine; elemene; emitefur; epirubicin; epristeride; estramustineanalogue; estrogen agonists; estrogen antagonists; etanidazole;etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide;filgrastim; finasteride; flavopiridol; flezelastine; fluasterone;fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane;fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathioneinhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;ilomastat; imiquimod; immunostimulant peptides; insulin-like growthfactor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetiumtexaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;marimastat; masoprocol; maspin; matrilysin inhibitors; matrixmetalloproteinase inhibitors; menogaril; merbarone; meterelin;methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine;mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide;mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;molgramostim; Erbitux, human chorionic gonadotrophin; mopidamol; mustardanticancer agent; mycaperoxide B; mycobacterial cell wall extract;myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin;nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim;nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitricoxide modulators; nitroxide antioxidant; nitrullyn; O⁶-benzylguanine;octreotide; okicenone; oligonucleotides; onapristone; ondansetron;ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxelderivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine;romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin;SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine;senescence derived inhibitor 1; sense oligonucleotides; signaltransduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine;tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomeraseinhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; translation inhibitors; tretinoin;triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron;turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors;ubenimex; urogenital sinus-derived growth inhibitory factor; urokinasereceptor antagonists; vapreotide; variolin B; velaresol; veramine;verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

[0192] In one embodiment of the invention, the compounds of theinvention can be used, not only to directly treat the disorder, but alsoto reduce the dose or toxicity of another chemotherapeutic. For example,the compounds of the invention can be administered to reducegastrointestinal toxicity associated with a topoisomerase inhibitor,such as irinotecan.

4.6. Biological Assays

[0193] Compounds having PDE 4, TNF-α, and MMP inhibitory activity can beassayed using methods commonly known in the art including, but notlimited to, enzyme immunoassay, radioimmunoassay, immunoelectrophoresis,and affinity labeling. Further assays which can be utilized includeLPS-induced TNF and PDE4 enzymatic assays and the methods set out inInternational Patent Publication Nos. WO 01/90076 A1 WO 01/34606 A1 eachof which are incorporated herein in their entireties by reference.

[0194] PBMC from normal donors are obtained by Ficoll-Hypaque densitycentrifugation. Cells are cultured in RPMI supplemented with 10%,AB+serum, 2 mM L-glutamine, 100 U/mL penicillin and 100 mg/mLstreptomycin.

[0195] The test compounds are dissolved in dimethylsulfoxide (SigmaChemical), further dilutions are done in supplemented RPMI. The finaldimethylsulfoxide concentration in the presence or absence of drug inthe PBMC suspensions is 0.25 wt %. The test compounds are assayed athalf-log dilutions starting in 50 mg/mL. The test compounds are added toPBMC (10⁶ cells/mL) in 96 wells plates one hour before the addition ofLPS.

[0196] PBMC (10⁶ cells/mL) in the presence or absence of test compoundsare stimulated by treatment with 1 mg/mL of LPS from Salmonellaminnesota R595 (List Biological Labs, Campbell, Calif.). Cells are thenincubated at 37° C. for 18-20 hours. Supernatants are harvested andassayed immediately for TNFα levels or kept frozen at −70° C. (for notmore than 4 days) until assayed.

[0197] The concentration of TNFα in the supernatant is determined byhuman TNFα ELISA kits (ENDOGEN, Boston, Mass.) according to themanufacturer's directions.

[0198] Phosphodiesterase can be determined in conventional models. Forexample, using the method of Hill and Mitchell, U937 cells of the humanpromonocytic cell line are grown to 1×10⁶ cells/mL and collected bycentrifugation. A cell pellet of 1×10⁹ cells is washed in phosphatebuffered saline and then frozen at −70° C. for later purification orimmediately lysed in cold homogenization buffer (20 mM Tris-HCl, pH 7.1,3 mM 2-mercaptoethanol, 1 mM magnesium chloride, 0.1 mM ethyleneglycol-bis-(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), 1 μMphenyl-methylsulfonyl fluoride (PMSF), and 1 μg/mL leupeptin). Cells arehomogenized with 20 strokes in a Dounce homogenizer and supernatantcontaining the cytosolic fraction are obtained by centrifugation. Thesupernatant then is loaded onto a Sephacryl S-200 column equilibrated inhomogenization buffer. Phosphodiesterase is eluted in homogenizationbuffer at a rate of approximately 0.5 mL/min and fractions are assayedfor phosphodiesterase activity −/+rolipram. Fractions containingphosphodiester-ase activity (rolipram sensitive) are pooled andaliquoted for later use.

[0199] The phosphodiesterase assay is carried out in a total volume of100 μl containing various concentration of test compounds, 50 mMTris-HCl, pH 7.5, 5 mM magnesium chloride, and 1 μM cAMP of which 1% was3H cAMP. Reactions are incubated at 30° C. for 30 minutes and terminatedby boiling for 2 minutes. The amount of phosphodiesterase IV containingextract used for these experiments is predetermined such that reactionsare within the linear range and consumed less than 15% of the totalsubstrate. Following termination of reaction, samples are chilled at 4°C. and then treated with 10 μl 10 mg/mL snake venom for 15 min at 30° C.Unused substrate then is removed by adding 200 μl of a quaternaryammonium ion exchange resin (AG1-X8, BioRad) for 15 minutes. Samplesthen are spun at 3000 rpm, 5 min and 50 μl of the aqueous phase aretaken for counting. Each data point is carried out in duplicate andactivity is expressed as percentage of control. The IC₅₀ of the compoundthen is determined from dose response curves of a minimum of threeindependent experiments.

[0200] The following examples are offered by way of illustration and arenot intended to limit the scope of the invention.

5. EXAMPLES

[0201] Reagents and solvents used below can be obtained from commercialsources such as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR and¹³C-NMR spectra were recorded on a Bruker AC 250 MHz NMR spectrometer.Significant peaks are tabulated in the order: chemical shift,multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; br s, broad singlet), coupling constant(s) in Hertz (Hz) andnumber of protons.

5.1. Example 1

[0202] (1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-amide

[0203] A solution of(3R)-3-amino-3-(3-ethoxy-4-methoxy-phenyl)-propan-1-ol (1.1 g, 4.9mmol), 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methylester (1.5 g, 4.8 mmol) and triethylamine (0.75 mL, 5.4 mmol) in DMF (10mL) was heated at 100° C. for 18 h. The solvent was removed in vacuo.The residue was extracted with ethyl acetate (50 mL) and water (50 mL).The organic layer was washed with HCl (1N, 50 mL), brine (50 mL), anddried over MgSO₄. The solvent was removed in vacuo to give an oil. Theoil was stirred in ether (5 mL) and hexane (5 mL) to give a suspension.The suspension was filtered to give (1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas a white solid (1.3 g, 64% yield): mp, 103-105° C.; ¹H NMR (CDCl₃) δ0.86-0.93 (m, 2H, CH₂), 1.08-1.12 (m, 2H, CH₂), 1.44 (t, J=7 Hz, 3H,CH₃), 1.64-1.73 (m, 1H, CH), 2.11-2.32 (m, 2H, CH₂), 3.37 (dd, J=4, 9Hz, 1H, OH), 3.50-3.59 (m, 1H, CHH), 3.74-3.79 (m, 2H, NCHH, CHH), 3.80(s, 3H, CH₃), 4.06 (q, J=7 Hz, 2H, CH₂), 4.16 (d, J=18 Hz, 1H, NCHH),6.65 (dd, J=4, 11 Hz, 1H, NCH), 6.83-6.99 (m, 4H, Ar), 7.44 (t, J=8 Hz,1H, Ar), 8.45 (d, J=8 Hz, 1H, Ar), 10.52 (s, 1H, NH); ¹³C NMR (CDCl₃) δ8.35, 14.77, 16.22, 33.85, 46.23, 50.52, 55.98, 58.59, 64.55, 111.36,112.99, 116.77, 116.99, 117.83, 119.77, 130.73, 133.37, 138.05, 141.49,148.62, 149.25, 170.33, 172.76; Anal Calcd for C₂₄H₂₈N₂O₅: C, 67.91; H,6.65; N, 6.60. Found: C, 67.92; H, 6.67; N, 6.37.

5.2. Example 2

[0204](1R)-2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-7-nitro-2,3-dihydro-Isoindol-1-one

[0205](1R)-2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-7-nitro-2,3-dihydro-isoindol-1-onewas prepared by the procedure of Example 1 from(3R)-3-amino-3-(3-ethoxy-4-methoxy-phenyl)-propan-1-ol (3.0 g, 13 mmol),2-bromomethyl-6-nitro-benzoic acid methyl ester (3.6 g, 13 mmol) andtriethylamine (2 mL, 14 mmol) in DMF (40 mL) to give a yellow solid (4.1g, 81% yield): ¹H NMR (CDCl₃) δ 1.44 (t, J=7 Hz, 3H, CH₃), 2.13-2.31 (m,2H, CH₂), 3.54-3.59 (m, 1, CHH), 3.71-3.77 (m, 1H, NCHH), 3.87 (s, 3H,CH₃), 3.94 (d, J=16 Hz, 1H, NCHH), 4.06 (q, J=7 Hz, 2H, CH₂), 4.26 (d,J=16 Hz, 1H, NCHH), 5.70 (dd, J=4, 11 Hz, 1H, NCH), 6.85-6.99 (m, 3H,Ar), 7.55-7.77 (m, 3H, Ar); ¹³C NMR (CDCl₃) δ 14.76, 33.92, 45.80,51.30, 55.98, 58.65, 64.63, 65.84, 111.39, 113.22, 119.75, 122.91,124.13, 126.74, 130.66, 132.11, 143.84, 146.66, 148.68, 149.33, 164.22.

5.3. Example 3

[0206](3R)-(tert-Butoxy)-N-{3-(3-ethoxy-4-methoxyphenyl)-3-[7-nitro-1-oxoisoindolin-2-yl]-propyl}carbonylamino(tert-butoxy)formate

[0207] To a solution of(1R)-2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-7-nitro-2,3-dihydro-isoindol-1-one(4.1 g, 11 mmol), (tert-butoxy)carbonylamino (tert-butoxy)formate (3.0g, 13 mmol), and triphenylphosphine in THF (40 mL) was added diisopropylazodicarboxylate (2.6 mL, 13 mmol) at room temperature. After 30 min,the solvent was removed in vacuo. The residue was purified withchromatography (Silica Gel) to give(3R)-(tert-butoxy)-N-{3-(3-ethoxy-4-methoxyphenyl)-3-[7-nitro-1-oxoisoindolin-2-yl]-propyl}carbonylamino(tert-butoxy)formate (5 g, 78% yield): ¹H NMR (CDCl₃) δ 1.41 (s, 9H,3CH₃), 1.42 (t, J=7 Hz, 3H, CH₃), 1.51 (s, 9H, 3CH₃), 2.39-2.52 (m, 2H,CH₂), 3.59-3.69 (m, 2H, CH₂), 3.84 (s, 3H, CH₃), 4.06 (q, J=7 Hz, 2H,CH₂), 4.11 (d, J=16 Hz, 1H, NCHH), 4.43 (d, J=16 Hz, 1H, NCHH), 5.47(dd, J=7, 9 Hz, 1H, NCH), 6.81 (d, J=8 Hz, 1H, Ar), 6.94-6.99 (m, 2H,Ar), 7.55-7.77 (m, 3H, Ar).

5.4. Example 4

[0208](3R)-(tert-Butoxy)-N-{3-[7-(cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}carbonylamino(tert-butoxy)formate

[0209] A solution of(3R)-N-[3-(7-amino-1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propyl](tert-butoxy)carbonylamino(tert-butoxy)formate (4.1 g, 7.2 mmol), cyclopropanecarbonyl chloride(0.80 mL, 8.8 mmol) and triethylamine (1.3 mL, 9.3 mmol) in THF (20 mL)was heated at reflux for 2 h. The solution was extracted with ethylacetate (100 mL) and sodium hydrogen carbonate (sat, 50 mL). The organiclayer was washed with sodium hydrogen carbonate (sat, 50 mL), brine (50mL), and dried over MgSO₄. The solvent was removed in vacuo to give(3R)-(tert-butoxy)-N-{3-[7-(cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}carbonylamino(tert-butoxy)formate as a white solid (4.4 g, 95% yield): mp, 153-155°C.; ¹H NMR (CDCl₃) δ 0.84-0.92 (m, 2H, CH₂), 1.06-1.13 (m, 2H, CH₂),1.42 (s, 9H, 3CH₃), 1.43 (t, J=7 Hz, 3H, CH₃), 1.50 (s, 9H, 3CH₃),1.65-1.73 (m, 1H, CH), 2.38-2.48 (m, 2H, CH₂), 3.61-3.73 (m, 2H, CH₂),3.85 (s, 3H, CH₃), 4.03 (d, J=18 Hz, 1H, NCHH), 4.04 (q, J=7 Hz, 2H,CH₂), 4.33 (d, J=18 Hz, 1H, NCHH), 5.47 (t, J=7 Hz, 1H, NCH), 6.81-7.00(m, 4H, Ar), 7.42 (t, J=8 Hz, 1H, Ar), 8.42 (d, J=8 Hz, 1H, Ar), 10.61(s, 1H, NH); ¹³C NMR (CDCl₃) δ 8.21, 14.76, 16.16, 27.58, 28.03, 29.14,46.21, 47.93, 52.21, 55.96, 58.45, 64.54, 82.57, 85.01, 111.45, 112.58,116.73, 117.54, 117.67, 119.37, 131.36, 133.08, 138.02, 141.39, 148.59,149.12, 152.21, 154.61, 169.50, 172.70; Anal Calcd for C₃₄H₄₅N₃O₉: C,63.83; H, 7.09; N, 6.57. Found: C, 63.84; H, 7.03; N, 6.44.

5.5. Example 5

[0210]N-[3-(7-Amino-1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propyl](tert-butoxy)carbonylamino(tert-butoxy)formate

[0211] A mixture of(tert-butoxy)-N-{3-[7-nitro-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}carbonylamino(tert-butoxy)formate (5.0 g, 8.3 mmol) and Pd/C (500 mg) in ethylacetate (60 mL) was shaken under hydrogen for 24 h. The suspension wasfiltered thru a pad of Celite. The solvent was removed in vacuo to giveN-[3-(7-amino-1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propyl](tert-butoxy)carbonylamino(tert-butoxy)formate as a yellow solid (4.4 g, 93% yield): mp, 85-87°C.; ¹H NMR (CDCl₃) δ 1.42 (s, 9H, 3CH₃), (t, J=7 Hz, 3H, CH₃), 1.49 (s,9H, 3CH₃), 2.34-2.44 (m, 2H, CH₂), 3.59-3.70 (m, 2H), CH₂), 3.82 (s, 3H,CH₃), 3.94 (d, J=16 Hz, 1H, NCHH), 4.02 (q, J=7 Hz, 2H, CH₂), 4.24 (d,J=16 Hz, 1H, NCHH), 5.23 (brs, 2H, NH₂), 5.39 (t, J=8 Hz, 1H, NCH), 5.52(d, J=8 Hz, 1H, Ar), 5.58 (d, J=8 Hz, 1H, Ar), 6.80 (d, J=8 Hz, 1H, Ar),6.89-6.92 (m, 2H, Ar), 7.16 (t, J=8 Hz, 1H, Ar); ¹³C NMR (CDCl₃) δ14.74, 27.58, 28.05, 28.99, 45.99, 48.18, 51.58, 55.93, 64.46, 82.44,84.87, 110.99, 111.37, 112.70, 113.31, 115.29, 119.32, 131.93, 132.59,142.54, 146.00, 148.48, 148.89, 152.20, 154.60, 170.00; Anal Calcd forC₃₀H₄₁N₃O₈: C, 63.03; H, 7.23; N, 7.35. Found: C, 63.07; H, 7.27; N,7.08.

5.6. Example 6

[0212] (3R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-amide

[0213] A solution of(3R)-(tert-butoxy)-N-{3-[7-(cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}carbonylamino(tert-butoxy)formate (4.1 g, 6.4 mmol) in methylene chloride (20 mL) andtrifluoroacetic acid (9 mL) was stirred at room temperature for 1.5 h.The solvent was removed in vacuo to give a yellow oil. The oil wasextracted with ethyl acetate (50 mL) and sodium hydrogen carbonate (sat,50 mL). The organic layer was washed with brine (50 mL), and dried overMgSO₄. The solvent was removed in vacuo to give an oil. The oil wasstirred in ether (15 mL) to give a suspension. The suspension wasfiltered to give (3R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas white solid (2.1 g, 75% yield): mp, 136-138° C.; ¹H NMR (CDCl₃) δ0.84-0.91 (m, 2H, CH₂), 1.06-1.14 (m, 2H, CH₂), 1.43 (t, J=7 Hz, 3H,CH₃), 1.64-1.71 (m, 1H, CH), 2.23-2.45 (m, 2H, CH₂), 2.99 (t, J=7 Hz,2H, CH₂), 3.85 (s, 3H, CH₃), 3.95 (d, J=16 Hz, 1H, NCHH), 4.06 (q, J=7Hz, 2H, CH₂), 4.26 (d, J=16 Hz, 1H, NCHH), 5.57 (dd, J=6, 10 Hz, 1H,NCH), 6.81-6.99 (m, 4H, Ar), 7.41 (t, J=8 Hz, 1H, Ar), 8.42 (d, J=8 Hz,1H, Ar), 10.57 (s, 1H, NH); ¹³C NMR (CDCl₃) δ 8.27, 14.77, 16.19, 28.83,45.79, 50.40, 51.49, 55.96, 64.57, 111.44, 112.84, 116.73, 117.39,117.73, 119.52, 131.27, 133.13, 137.99, 141.36, 148.62, 149.18, 169.55,172.72; Anal Calcd for C₂₄H₂₉N₃O₅: C, 65.59; H, 6.65; N, 9.56. Found: C,65.30; H, 6.63; N, 9.21.

5.7. Example 7

[0214] (1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-amide

[0215] A solution of (3R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(340 mg, 0.77 mmol) and 2,2,2-trifluoroethyl formate (1 g) in THF (4 mL)was heated to reflux for 3 h. The solvent was removed in vacuo. Theresidue was extracted with ethyl acetate (50 mL) and sodium hydrogencarbonate (sat, 50 mL). The organic layer was washed with brine (50 mL)and dried over MgSO₄. The solvent was removed in vacuo to give a solid.The solid was purified with prep HPLC to give(1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas a white solid (220 mg, 61% yield): mp, 102-104° C.; ¹H NMR (DMSO-d6)δ 0.87-0.89 (m, 4H, 2CH₂), 1.31 (t, J=7 Hz, 3H, CH₃), 1.73-1.80 (m, 1H,CH), 2.31-2.38 (m, 2H, CH₂), 3.43-3.53 (m, 2H, CH₂), 3.73 (s, 3H, CH₃),3.98-4.07 (m, 2H), CH₂), 4.14 (d, J=18 Hz, 1H, NCHH), 4.54 (d, J=18 Hz,1H, NCHH), 5.26-5.29 (m, 1H, NCH), 6.93-6.96 (m, 3H, Ar), 7.18 (d, J=8Hz, 1H, Ar), 7.49 (t, J=8 Hz, 1H, Ar), 7.85 (s, 0.6H, CH), 8.22 (d, J=8Hz, 1H, Ar), 8.24 (s, 0.4H, CH), 9.64 (s, 0.5H, NH), 10.07 (s, 0.5H,NH), 10.57 (s, 1H, NH); ¹³C NMR (DMSO-d6) δ 7.45, 14.65, 15.51, 28.77,46.31, 52.13, 55.91, 64.38, 112.99, 113.74, 116.93, 117.35, 117.54,120.02, 132.03, 132.60, 137.18, 142.23, 148.35, 149.17, 168.60, 171.59;Anal Calcd for C₂₅H₂₉N₃O₆+0.3 H₂O: C, 63.49; H, 6.31; N, 8.89, H₂O,1.14. Found: C, 63.11; H, 6.16; N, 8.73, H₂O, 0.77.

5.8. Example 8

[0216](1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-acetamide

[0217](1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamidewas prepared by the procedure of Example 7 fromN-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide(0.7 g, 1.7 mmol) and 2,2,2-trifluoroethyl formate (2.2 g, 17 mmol) inTHF (10 mL) to give a white solid (480 mg, 64% yield): mp: 79-81° C. ¹HNMR (DMSO-d6) δ 1.31 (t, J=7 Hz, 3H, CH₃), 1.99 (s, 3H, CH₃), 2.32-2.42(m, 2H, CH₂), 3.40-3.52 (m, 2H, CH₂), 3.73 (s, 3H, CH₃), 3.98-4.02 (m,2H, CH₂), 4.14 (d, J=17 Hz, 1H, NCHH), 4.54 (d, J=17 Hz, 1H, NCHH),5.23-5.28 (m, 1H, NCH), 6.92-6.96 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar),7.50 (t, J=8 Hz, 1H, Ar), 7.83 (s, 0.5H, CH), 8.24-8.27 (m, 1.5H, Ar,CH), 9.64 (s, 0.5H, OH), 10.07 (s, 0.5H, OH), 10.30 (s, 1H, NH); ¹³C NMR(DMSO-d6) δ 14.70, 24.50, 28.34, 28.52, 43.39, 45.81, 46.19, 46.74,51.14, 51.92, 55.45, 63.81, 111.97, 112.39, 116.63, 117.39, 119.66,131.60, 132.70, 137.02, 142.21, 142.30, 147.96, 148.54, 157.35, 168.21,168.38, 168.51; Anal Calcd for C₂₃H₂₇N₃O₆+0.4 H₂O: C, 61.57; H, 6.25; N,9.36; H₂O, 1.61. Found: C, 61.77; H, 6.18; N, 8.97; H₂O, 0.55.

5.9. Example 9

[0218](1R)-N-{2-[-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-Isobutyramide

[0219](1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramidewas prepared by the procedure of Example 7 fromN-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide(1.6 g, 3.6 mmol) and 2,2,2-trifluoroethyl formate (5 g, 39 mmol) in THF(20 mL) to give a white solid (0.7 g, 41% yield): mp: 81-83° C. ¹H NMR(DMSO-d6) δ 1.18 (d, J=7 Hz, 6H, 2CH₃), 1.31 (t, J=7 Hz, 3H, CH₃),2.34-2.38 (m, 2H, CH₂), 2.56-2.65 (m, 1H, CH), 3.39-3.51 (m, 2H, CH₂),3.73 (s, 3H, CH₃), 3.96-4.05 (m, 2H, CH₂), 4.16 (d, J=17 Hz, 1H, NCHH),4.55 (d, J=17 Hz, 1H, NCHH), 5.25-5.29 (m, 1H, NCH), 6.93-6.97 (m, 3H,Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 7.83 (s, 0.5H,CH), 8.25 (s, 0.5H, CH), 8.28 (d, J=8 Hz, 1H, Ar), 9.63 (s, 0.5H, OH),10.07 (s, 0.5H, OH), 10.47 (s, 1H, NH); ¹³C NMR (DMSO-d6) δ 14.69,19.16, 19.21, 28.39, 28.60, 35.94, 43.35, 45.92, 46.26, 46.73, 51.17,51.92, 55.44, 63.78, 111.97, 112.34, 116.55, 117.54, 117.58, 119.68,131.54, 132.16, 151.12, 142.28, 147.94, 148.53, 157.36, 161.80, 168.37,168.53, 174.93; Anal Calcd for C₂₅H₃₁N₃O₆+0.4 H₂O: C, 62.98; H, 6.72; N,8.81; H₂O, 1.51. Found: C, 62.96; H, 6.80; N, 8.84; H₂O, 1.48.

5.10. Example 10

[0220](1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-1,3-dioxo-2,3-dihydro-1H-Isoindol-4-yl}-acetamide

[0221] To a solution of(1R)-N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide(350 mg, 0.82 mmol) in methylene chloride (3 mL) was added a solution ofacetyl formate (84 mg) in methylene chloride (1 mL) at 0° C. After 1 h,the mixture was extracted with ethyl acetate (25 mL) and water (25 mL).The organic layer was washed with brine (20 mL) and dried over MgSO₄.The solvent was removed in vacuo. The residue was purified with prepHPLC to give(1R)-N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamideas a white solid (90 mg, 24% yield): mp: 96-98° C.; ¹H NMR (CDCl₃) δ1.46 (t, J=7 Hz, 3H, CH₃), 2.26 (s, 3H, CH₃), 2.81-2.83 (m, 2H, CH₂),3.56 (t, J=6 Hz, 2H, CH₂), 3.85 (s, 3H, CH₃), 4.10 (q, J=7 Hz, 2H, CH₂),5.25 (t, J=8 Hz, 1H), NCH), 6.82 (d, J=8 Hz, 1H, Ar), 7.06-7.09 (m, 2H,Ar), 7.45 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 7.72 (s, 1H,CH), 8.75 (d, J=8 Hz, 1H, Ar), 9.49 (s, 1H, NH); ¹³C NMR (CDCl₃) δ14.73, 24.95, 28.35, 46.61, 51.92, 55.93, 64.46, 111.37, 112.79, 115.21,118.05, 120.63, 124.90, 130.33, 131.09, 136.02, 137.47, 148.48, 149.40,155.73, 167.72, 169.27, 170.07; Anal Calcd for C₂₃H₂₅N₃O₇+0.3 H₂O: C,59.95; H, 5.60; N, 9.12; H₂O, 1.17. Found: C, 59.94; H, 5.59; N, 8.98;H₂O, 1.22.

5.11. Example 11

[0222](1R)-N-{2-[3-(N-Acetoxy-N-formyl-amino)-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-Isobutyramide

[0223] To a solution of(1R)-N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide(300 mg, 0.64 mmol) in acetonitrile (6 mL) was added acetic anhydride(0.1 mL, 1 mmol) at room temperature. After 4 h, the solvent was removedin vacuo and the residue was purified by chromatography (Silica Gel) togive(1R)-N-{2-[3-(N-acetoxy-N-formyl-amino)-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramideas a white solid (0.21 g, 64% yield): mp: 72-74° C. ¹H NMR (DMSO-d6) δ1.17 (d, J=7 Hz, 6H, 2CH₃), 1.31 (t, J=7 Hz, 3H, CH₃), 2.19 (s, 3H,CH₃), 2.32-2.50 (m, 2H, CH₂), 2.59-2.68 (m, 1H, CH), 3.60-3.67 (m, 2H,CH₂), 3.73 (s, 3H, CH₃), 3.99-4.09 (m, 3H, NCHH, CH₂), 4.56 (d, J=17 Hz,1H, NCHH), 5.30-5.38 (m, 1H, NCH), 6.88-6.93 (m, 3H, Ar), 7.18 (d, J=8Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 8.11 (s, 1H, CH), 8.29 (d, J=8Hz, 1H, Ar), 10.47 (s, 1H, NH); ¹³C NMR (DMSO-d6) δ 14.69, 18.01, 19.16,28.87, 35.94, 45.87, 46.13, 51.18, 55.45, 63.80, 111.96, 112.32, 116.55,117.55, 119.76, 131.30, 132.79, 137.14, 142.32, 147.99, 148.59, 157.50,163.00, 167.31, 168.57, 174.94; Anal Calcd for C₂₇H₃₃N₃O₇+0.2 H₂O: C,62.95; H, 6.53; N, 8.16; H₂O, 0.70. Found: C, 62.81; H, 6.63; N, 7.92;H₂O, 0.59.

5.12. Example 12

[0224](1R)-N-{2-[3-(N-Aminocarbonyl-N-hydroxy-amino)-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-Isobutyramide

[0225] To a solution of(1R)-N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide(1.3 g, 2.6 mmol) in water (30 mL) was added a solution of potassiumcyanate (442 mg, 5.5 g) in water (10 mL) at room temperature. After 1 h,the mixture was extracted with ethyl acetate (50 mL). The organic layerwas washed with HCl (1N, 25 mL), brine (25 mL) and dried over MgSO₄. Thesolvent was removed in vacuo and the residue was purified by prep HPLCto give(1R)-N-{2-[3-(N-aminocarbonyl-N-hydroxy-amino)-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramideas a white solid (0.70 g, 55% yield): mp: 137-139° C. ¹H NMR (DMSO-d6) δ1.18 (d, J=7 Hz, 6H, 2CH₃), 1.31 (t, J=7 Hz, 3H, CH₃), 2.25-2.34 (m, 2H,CH₂), 2.51-2.66 (m, 1H, CH), 3.22-3.40 (m, 2H, CH₂), 3.73 (s, 3H, CH₃),3.95-4.06 (m, 2H, CH₂), 4.10 (d, J=18 Hz, 1H, NCHH), 4.55 (d, J=18 Hz,1H, NCHH), 5.26 (t, J=8 Hz, 1H, NCH), 6.34 (s, 2H, NH₂), 6.92-6.98 (m,3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 8.29 (d,J=8 Hz, 1H, Ar), 9.34 (s, 1H, CH), 10.48 (s, 1H, NH); ¹³C NMR (DMSO-d6)δ 14.70, 19.18, 28.73, 35.94, 46.25, 47.22, 52.04, 55.43, 63.76, 111.94,112.40, 116.55, 117.52, 117.60, 119.58, 131.99, 132.73, 137.12, 142.20,147.89, 148.43, 161.57, 168.34, 174.93; Anal Calcd for C₂₅H₃₂N₄O₆+0.9H₂O: C, 59.96; H, 6.80; N, 11.19; H₂O, 3.24. Found: C, 60.16; H, 6.58;N, 10.81; H₂O, 3.24.

5.13. Example 13

[0226] (1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-amide

[0227] A solution of (1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(460 mg, 1 mmol) and acetic anhydride (0.2 mL) in acetonitrile (6 mL)was stirred at room temperature for 16 h. The solvent was removed invacuo. The residue was extracted with ethyl acetate (50 mL) and sodiumhydrogen carbonate (sat, 50 mL). The organic layer was washed with brine(50 mL) and dried over MgSO₄. The solvent was removed in vacuo to give(1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas a white solid (370 mg, 72% yield): mp, 106-108° C.; ¹H NMR (DMSO-d6)δ 0.87-0.89 (m, 4H, 2CH₂), 1.31 (t, J=7 Hz, 3H, CH₃), 1.76-1.80 (m, 1H,CH), 2.19 (s, 3H, CH₃), 2.27-2.40 (m, 2H, CH₂), 3.65-3.68 (m, 2H), CH₂),3.73 (s, 3H, CH₃), 3.97-4.08 (m, 3H, NCHH, CH₂), 4.56 (d, J=18 Hz, 1H,NCHH), 5.20-5.39 (m, 1H, NCH), 6.89-6.93 (m, 3H, Ar), 7.17 (d, J=8 Hz,1H, Ar), 7.49 (t, J=8 Hz, 1H, Ar), 8.12 (s, 1H, CH), 8.23 (d, J=8 Hz,1H, Ar), 10.57 (s, 1H, NH); Anal Calcd for C₂₇H₃₁N₃O₇+0.3 H₂O: C, 62.97;H, 6.19; N, 8.16, H₂O, 1.05. Found: C, 63.03; H, 6.12; N, 7.98, H₂O,0.81.

5.14. Example 14

[0228](N-{3-[7-(Cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}acetylamino)acetate

[0229] A solution of cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(0.3 g, 0.7 mmol) and acetic hydride (68 μL, 0.7 mmol) in methylenechloride (2 mL) was stirred at room temperature for 1 h. The mixture wasextracted with methylene chloride (20 mL) and sodium hydrogen carbonate(sat, 20 mL). The organic layer was concentrated in vacuo to give anoil. The oil was purified with prep HPLC to give(N-{3-[7-(cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}acetylamino)acetate as a white solid (25 mg, 7% yield): mp, 123-125° C.; ¹H NMR(CDCl₃) δ 0.87-0.91 (m, 2H, CH₂), 1.08-1.39 (m, 2H, CH₂), 1.45 (t, J=7Hz, 3H, CH₃), 1.63-1.71 (m, 1H, CH), 1.98 (s, 3H, CH₃), 2.20 (s, 3H,CH₃), 2.39-2.48 (m, 2H, CH₂), 3.73 (t, J=7 Hz, 2H, CH₂), 3.86 (s, 3H,CH₃), 4.02 (d, J=16 Hz, 1H, NCHH), 4.08 (q, J=7 Hz, 2H, CH₂), 4.34 (d,J=16 Hz, 1H, NCHH), 5.41 (t, J=8 Hz, 1H, NCH), 6.82-6.95 (m, 3H, Ar),7.00 (d, J=8 Hz, 1H, Ar), 7.43 (t, J=8 Hz, 1H, Ar), 8.43 (d, J=8 Hz, 1H,Ar), 10.58 (s, 1H, NH); ¹³C NMR (CDCl₃) δ 8.26, 14.78, 16.19, 18.46,20.26, 29.09, 46.04, 46.69, 52.12, 55.97, 64.56, 111.42, 112.47, 116.82,117.41, 117.71, 119.45, 130.92, 133.21, 138.00, 141040, 148.64, 149.21,168.47, 169.54, 172.67; Anal Calcd for C₂₈H₃₃N₃O₇: C, 64.23; H, 6.35; N,8.03. Found: C, 63.87; H, 6.37; N, 7.95.

5.15. Example 15

[0230] (1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(formyl-hydroxy-amino)-butyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-amide

[0231] To a solution of(1R)-[1-(3-ethoxy-4-methoxy-phenyl)-3-oxo-butyl]-carbamic acidtert-butyl ester (1.0 g, 3.1 mol) in ethanol (10 mL) and pyridine (1 mL)was added hydroxylamine (1 g, 14 mmol). The solution was heated toreflux for 10 min. The solvent was removed iii vacuo. The residue wasextracted with methylene chloride (50 mL) and HCl (0.1N, 25 mL). Theorganic layer was washed with brine (50 mL) and dried over MgSO₄. Thesolvent was removed in vacuo to give(1R)-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyimino-butyl]-carbamic acidtert-butyl estercyclopropanecarboxylic acid as a white solid (1 g),which was used in the next step without further purification. A solutionof crude(1R)-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyimino-butyl]-carbamic acidtert-butyl estercyclopropanecarboxylic acid (1 g) in trifluoroaceticacid (3 mL) and methylene chloride (3 mL) was stirred at roomtemperature for 30 min. The solvent was removed in vacuo to give an oil.A solution of the crude oil,2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester(1.0 g, 3.2 mmol) and triethyl amine (1.0 mL, 7.2 mmol) in DMF (10 mL)was heated at 100° C. for 19 h. The solvent was removed in vacuo. Theresidue was extracted with methylene chloride (50 mL) and water (25 mL).The organic layer was washed with brine (50 mL) and dried over MgSO₄.The solvent was removed in vacuo. The residue was purified withchromatography (Silica Gel) to give (1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyimino-butyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideas a white solid (540 mg). To a solution of (1R)-cyclopropanecarboxylicacid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyimino-butyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide(540 mg, 1.2 mmol) in THF (5 mL) and ethanol (5 mL) was addedborane-pyridine (0.5 mL, 4 mmol) at room temperature and kept for 2 h.The mixture was poured to sodium hydrogen carbonate (sat, 25 mL). Themixture was extracted with methylene chloride (2×30 mL). The organiclayer was washed with brine (25 mL) and dried over MgSO₄. The solventwas removed in vacuo to give an oil. The solution of the crude oil and2,2,2-trifluoroethyl formate (1.5 g, 12 mmol) in THF (10 mL) was heatedto reflux for 2 h. The solvent was removed in vacuo. The residue wasextracted with ethyl acetate (50 mL) and HCl (1N, 50 mL). The organiclayer was washed with brine (50 mL) and dried over MgSO₄. The solventwas removed in vacuo. The residue was purified with prep HPLC to give amixture of diastereomer of (1R)-cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(formyl-hydroxy-amino)-butyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amidein 1:2 ratio as a white solid (370 mg, 64% yield): mp, 142-144° C.; ¹HNMR (DMSO-d6) δ 0.87-0.89 (m, 4H, 2CH₂), 1.14-1.33 (m, 6H, 2 CH₃),1.72-1.79 (m, 1H, CH), 2.22-2.32 (m, 2H, CH₂), 3.72 (s, 3H, CH₃),3.60-3.80 (m, 1H, CH), 4.00-4.21 (m, 3H, CH₂, NCHH), 4.50-4.57 (m, 1H,NCHH), 5.19-5.24 (m, 1H, NCH), 6.85-6.97 (m, 3H, Ar), 7.16 (d, J=8 Hz,1H, Ar), 7.48 (t, J=8 Hz, 1H, Ar), [7.67 (s, OCH)], 7.89 (s, 1H, OCH),8.20-8.27 (m, 1H, Ar), 9.43-[9.47 (brs, OH)], 9.83 (brs, 1H, OH),10.56-10.58 (m, 1H, NH);

[0232]¹³C NMR (DMSO-d6) δ 7.41, 14.69, 15.54, 34.50, 35.09, 46.49,51.79, 55.99, 64.52, 113.21, 113.96, 116.90, 117.25, 117.74, 119.97,132.09, 132.64, 137.22, 142.23, 178.39, 149.21, 168.45, 168.79, 171.56;Anal Calcd for C₂₆H₃₁N₃O₆+0.5 H₂O: C, 63.66; H, 6.58; N, 8.57; H₂O,1.84. Found: C, 63.46; H, 6.51; N, 8.47; H₂O, 1.07.

5.16. Example 16

[0233] 50 mg Solid Tablets

[0234] Tablets, each containing 50 mg of(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide,can be prepared in the following manner: Constitutuents (for 1000tablets) (1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3- 50.0 g(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide lactose 50.7 g wheat starch 7.5 g polyethylene glycol 6000  5.0 g talc  5.0 g magnesium stearate 1.8 g demineralized water q.s.

[0235] The solid ingredients are first forced through a sieve of 0.6 mmmesh width. The active ingredient, lactose, talc, magnesium stearate andhalf of the starch then are mixed. The other half of the starch issuspended in 40 mL of water and this suspension is added to a boilingsolution of the polyethylene glycol in 100 mL of water. The resultingpaste is added to the pulverulent substances and the mixture isgranulated, if necessary with the addition of water. The granulate isdried overnight at 35° C., forced through a sieve of 1.2 mm mesh widthand compressed to form tablets of approximately 6 mm diameter which areconcave on both sides.

5.17. Example 17

[0236] 100 mg Solid Tablets

[0237] Tablets, each containing 100 mg of(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide,can be prepared in the following manner: Constitutuents (for 1000tablets) (1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3- 100.0 g(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide lactose 100.0 g wheat starch 47.0 g magnesium stearate  3.0 g

[0238] All the solid ingredients are first forced through a sieve of 0.6mm mesh width. The active ingredient, lactose, magnesium stearate andhalf of the starch then are mixed. The other half of the starch issuspended in 40 mL of water and this suspension is added to 100 mL ofboiling water. The resulting paste is added to the pulverised substancesand the mixture is granulated, if necessary with the addition of water.The granulate is dried overnight at 35° C., forced through a sieve of1.2 mm mesh width and compressed to form tablets of approximately 6 mmdiameter which are concave on both sides.

5.18. Example 18

[0239] 75 mg Chewable Tablets

[0240] Tablets for chewing, each containing 75 mg of(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide,can be prepared in the following manner: Composition (for 1000 tablets)(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-  75.0 g(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide mannitol 230.0 g lactose150.0 g talc  21.0 g glycine  12.5 g stearic acid  10.0 g saccharin  1.5g 5% gelatin solution q.s.

[0241] All the solid ingredients are first forced through a sieve of0.25 mm mesh width. The mannitol are the lactose are mixed, granulatedwith the addition of gelatin solution, forced through a sieve of 2 mmmesh width, dried at 50° C. and again forced through a sieve of 1.7 mmmesh width(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide,the glycine and the saccharin are carefully mixed, the mannitol, thelactose granulate, the stearic acid and the talc are added and the wholeis mixed thoroughly and compressed to form tablets of approximately 10mm diameter which are concave on both sides and have a breaking grooveon the upper side.

5.19. Example 19

[0242] 10 mg Tablets

[0243] Tablets, each containing 10 mg(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide,can be prepared in the following manner. Composition (for 1000 tablets)(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-  10.0 g(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide lactose 328.5 g corn starch 17.5 g polyethylene glycol 6000  5.0 g talc  25.0 g magnesium stearate 4.0 g demineralized water q.s.

[0244] The solid ingredients are first forced through a sieve of 0.6 mmmesh width. Then the active amide ingredient, lactose, talc, magnesiumstearate and half of the starch are intimately mixed. The other half ofthe starch is suspended in 65 mL and this suspension is added to aboiling solution of the polyethylene glycol in 260 mL of water. Theresulting paste is added to the pulverulent substances, and the whole ismixed and granulated, if necessary with the addition of water. Thegranulate is dried overnight at 35° C., forced through a sieve of 1.2 mmmesh width and compressed to form tablets of approximately 10 mmdiameter which are concave on both sides and have a breaking notch onthe upper side.

5.20. Example 20

[0245] 100 g Gelatin Capsules

[0246] Gelatin dry-filled capsules, each containing 100(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide,can be prepared in the following manner: Composition (for 1000 tablets)(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3- 100.0 g(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide microcrystalline cellulose 30.0 g sodium lauryl sulfate  2.0 g magnesium stearate  8.0 g

[0247] The sodium lauryl sulfate is sieved into(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramidethrough a sieve of 0.2 mm mesh width and the two components areintimately mixed for 10 minutes. The microcrystalline cellulose is thenadded through a sieve of 0.9 mm mesh width and the whole is againintimately mixed for 10 minutes. Finally, the magnesium stearate isadded through a sieve of 0.8 mm width and, after mixing for a further 3minutes, the mixture is introduced in portions of 140 mg each into size0 (elongated) gelatin dry-fill capsules.

5.21. Example 21

[0248] Injectable Solution

[0249] A 0.2% injection or infusion solution can be prepared, forexample, in the following manner:(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3- 5.0 g(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide sodium chloride 22.5 gphosphate buffer pH 7.4 300.0 g demineralized water to 2500.0 mL

[0250](1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramideis dissolved in 1000 mL of water and filtered through a microfilter. Thebuffer solution is added and the whole is made up to 2500 mL with water.To prepare dosage unit forms, portions of 1.0 or 2.5 mL each areintroduced into glass ampoules (each containing respectively 2.0 or 5.0mg of amide).

[0251] All publications and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference. Although the foregoinginvention has been described in some detail by way of illustration andexample for purposes of clarity of understanding, it will be readilyapparent to those of ordinary skill in the art in light of the teachingsof this invention that certain changes and modifications may be madethereto without departing from the spirit or scope of the appendedclaims.

1. A compound of formula (I):

wherein: Y is —C(O)—, —CH₂—, —CH₂C(O)— or —SO₂—; R₁ and R₂ are eachindependently C₁₋₈-alkyl, CF₂H, CF₃, CH₂CHF₂, cycloalkyl, or(C₁₋₈-alkyl)cycloalkyl; Z₁ is H, C₁₋₆-alkyl, NH₂, NR₃R₄ or OR₅; Z₂ is Hor C(O)R₅; X₁, X₂, X₃ and X₄ are each independently H, halogen, NO₂,OR₃, CF₃, C₁₋₆-alkyl, (C₀₋₄alkyl)-(C₃₋₆-cycloalkyl),(C₀₋₄-alkyl)-N—(R₈R₉), (C₀₋₄-alkyl)-NHC(O)—(R₈),(C₀₋₄-alkyl)-NHC(O)CH(R₈)(R₉), (C₀₋₄-alkyl)-NHC(O)N(R₈R₉),(C₀₋₄-alkyl)-NHC(O)O(R₈), (C₀₋₄-alkyl)-O—R₈, (C₀₋₄-alkyl)-imidazolyl,(C₀₋₄-alkyl)-pyrrolyl, (C₀₋₄-alkyl)-oxadiazolyl, (C₀₋₄-alkyl)-triazolylor (C₀₋₄-alkyl)-heterocycle; R₃, R₄, and R₅ are each independently H,C₁₋₆-alkyl, O—C₁₋₆-alkyl, phenyl, benzyl, or aryl; R₆ and R₇ areindependently H or C₁₋₆-alkyl; R₈ and R₉ are each independently H,C₁₋₉-alkyl, C₃₋₆-cycloalkyl, (C₁₋₆-alkyl)-(C₃₋₆-cycloalkyl),(C₀₋₆-alkyl)-N(R₄R₅), (C₁₋₆-alkyl)-OR₅, phenyl, benzyl, aryl,piperidinyl, piperizinyl, pyrolidinyl, morpholino, orC₃₋₇-heterocycloalkyl; or a pharmaceutically acceptable salt or solvatethereof.
 2. The compound of claim 1 wherein Y is —CH₂— or —C(O)—.
 3. Thecompound of claim 1 wherein Z₁ is H.
 4. The compound of claim 3 whereinR₆ is C₁₋₆-alkyl and R₇ is H.
 5. The compound of claim 1 wherein Z₂ isH, —C(O)CH₃ or —C(O)CH₂CH₃.
 6. The compound of claim 5 wherein X₄ isNHC(O)R₈.
 7. The compound of claim 5 wherein R₁ is CH₃ or CF₂H and R₂ isC₁₋₈-alkyl.
 8. The compound of claim 5 wherein Z₂ is H.
 9. The compoundof claim 1 wherein R₁ is CH₃ or CF₂H.
 10. The compound of claim 1wherein R₂ is CH₂CH₃, CH₃, CF₂H, CH₂-cyclopropyl, or cyclopentyl. 11.The compound of claim 1 wherein R₆ and R₇ are both H or one of R₆ and R₇is H and the other is CH₃.
 12. The compound of claim 1 wherein X₄ is—NHC(O)R₈ and X₁ is H or halogen.
 13. The compound of claim 1 whereinone of X₁, X₂, X₃, and X₄ is NHCOCH₂N(CH₃)₂, NHCON(CH₃)₂, NHCONH₂,NHCOCH₃, NHCOCH(R₈)N(R₇R₈) or OCH₃, and the rest of X₁, X₂, X₃, and X₄are H.
 14. The compound of claim 1, wherein the configuration ofstereocenter a is (S).
 15. The compound of claim 1, wherein theconfiguration of stereocenter a is (R).
 16. The compound of claim 1,wherein R₆ and R₇ are not same, and the configuration of stereocenter bis (S).
 17. The compound of claim 1, wherein R₆ and R₇ are not same, andthe configuration of stereocenter b is (R).
 18. A diastereomericallypure SS isomer of a compound of claim 1, substantially free of otherdiasteriomers, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof.
 19. A diastereomericallypure RS isomer of a compound of claim 1, substantially free of otherdiasteriomers, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof.
 20. A diastereomericallypure SR isomer of a compound of claim 1, substantially free of otherdiasteriomers, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof.
 21. A diastereomericallypure RR isomer of a compound of claim 1, substantially free of otherdiasteriomers, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof.
 22. A compound, where thecompound is:(3R)-(tert-Butoxy)-N-{3-[7-(cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}carbonylamino(tert-butoxy)formate;N-[3-(7-Amino-1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propyl](tert-butoxy)carbonylamino(tert-butoxy)formate; (1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide;(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide;(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide;(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide;(1R)-N-{2-[3-(N-Acetoxy-N-formyl-amino)-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide;(1R)-N-{2-[3-(N-Aminocarbonyl-N-hydroxy-amino)-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide;(1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide;(N-{3-[7-(Cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propyl}acetylamino)acetate; or (1R)-Cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(formyl-hydroxy-amino)-butyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide.23. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier, excipient, or diluent and a compound of formula (I):

wherein: Y is —C(O)—, —CH₂—, —CH₂C(O)— or —SO₂—; R₁ and R₂ are eachindependently C₁₋₈-alkyl, CF₂H, CF₃, CH₂CHF₂, cycloalkyl, or(C₁₋₈-alkyl)cycloalkyl; Z₁ is H, C₁₋₆-alkyl, NH₂, NR₃R₄ or OR₅; Z₂ is Hor C(O)R₅; X₁, X₂, X₃ and X₄ are each independently H, halogen, NO₂,OR₃, CF₃, C₁₋₆-alkyl, (C₀₋₄alkyl)-(C₃₋₆-cycloalkyl),(C₀₋₄-alkyl)-N—(R₈R₉), (C₀₋₄-alkyl)-NHC(O)—(R₈),(C₀₋₄-alkyl)-NHC(O)CH(R₈)(R₉), (C₀₋₄-alkyl)-NHC(O)N(R₈R₉),(C₀₋₄-alkyl)-NHC(O)O(R₈), (C₀₋₄-alkyl)-O—R₈, (C₀₋₄-alkyl)-imidazolyl,(C₀₋₄-alkyl)-pyrrolyl, (C₀₋₄-alkyl)-oxadiazolyl, (C₀₋₄-alkyl)-triazolylor (C₀₋₄-alkyl)-heterocycle; R₃, R₄, and R₅ are each independently H,C₁₋₆-alkyl, O—C₁₋₆-alkyl, phenyl, benzyl, or aryl; R₆ and R₇ areindependently H or C₁₋₆-alkyl; R₈ and R₉ are each independently H,C₁₋₉-alkyl, C₃₋₆-cycloalkyl, (C₁₋₆-alkyl)-(C₃₋₆-cycloalkyl),(C₀₋₆-alkyl)-N(R₄R₅), (C₁₋₆-alkyl)-OR₅, phenyl, benzyl, aryl,piperidinyl, piperizinyl, pyrolidinyl, morpholino, orC₃₋₇-heterocycloalkyl; or a pharmaceutically acceptable salt or solvatethereof.
 24. The pharmaceutical composition of claim 23 furthercomprising an additional therapeutic agent.
 25. The pharmaceuticalcomposition of claim 24 wherein the additional therapeutic agent is ananti-cancer agent or an anti-inflammatory agent.
 26. The pharmaceuticalcomposition of claim 25 wherein the anti-cancer agent is paclitaxel,cisplatin, tamoxifen, docetaxel, pirubicin, doxorubicin, ironetacen,leuprolide, bicalutamide, a goserlin implant, gemcitabine, sargramostimor a steroid. 27-57. Cancelled